CLINICAL TRIALS PROFILE FOR ENVARSUS XR

505(b)(2) Clinical Trials for ENVARSUS XR

This table shows clinical trials for potential 505(b)(2) applications. See the next table for all clinical trials

Trial Type	Trial ID	Title	Status	Sponsor	Phase	Start Date	Summary
New Formulation	NCT04489134 ↗	P-glypoprotein Inhibition Effect on the Pharmacokinetics of Two Tacrolimus Formulations: Prolonged and Extended-release	Not yet recruiting	Rennes University Hospital	Phase 2	2021-11-01	Tacrolimus is a drug administered orally available with different formulations: immediate release (Prograf®), prolonged-release (Advagraf®) and an extended-release one named LCP-Tacro (Envarsus®), formulated using the Melt-Dose process. Tacrolimus is a lipophilic macrolide drug able to passive transmembrane diffusion. Its bioavailability displays a large interindividual variability, from 9 to 43%. Indeed, tacrolimus is a substrate of P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4). P-gp is an efflux protein mainly located at the apex of the epithelia of the intestine, lymphocyte, kidney and blood-brain barrier. P-gp therefore limits the intestinal resorption of tacrolimus and also its diffusion into its target compartment (i.e the lymphocyte. The expression of this protein is different throughout the digestive tract with maximum expression at the ileal level. CYP3A4 is a coenzyme that is responsible of more than 90% of the metabolism of tacrolimus, at the digestive and hepatic level. Both P-gp and CYP3A4 play a role in tacrolimus absorption/diffusion process. A new formulation of tacrolimus, LCP-Tacro, (Envarsus®) was approved in 2014. Its efficacy was compared to Prograf® in two phase III de novo or switch Prograf® trials in kidney transplantation. With tacrolimus, there is a strong inter-individual pharmacokinetic variability which, to date, has not been fully characterized. Variations in bioavailability may partly explain this high variability. The different formulations are resorbed at distinct gastrointestinal sites which could explain different absorptions between Prograf/Advagraf and LCP-Tacro forms. These findings raise the question of the role of P-gp in explaining the difference in bioavailability between formulations. The use of a P-gp inhibitor could therefore have a different impact on exposure to different galenic formulations. Verapamil is an inhibitor of P-gp and CYP 3A4, which is frequently prescribed and recommended by FDA for drug-drug interaction studies aiming at evaluating P-gp substrates, used in healthy volunteers at dosages up to 240 mg/D13-14. Otherwise, verapamil-tacrolimus interaction has been characterized in vitro. It has also been shown that inhibitory effect of verapamil at a single dose of 120 mg administered one hour prior to the administration of a P-gp substrate exhibited an optimum power of inhibition. The safety of Advagraf® and Envarsus® administrations have already been subjected to several phase I trials in healthy volunteers reinforcing the knowledge of their safety profile. The aim of the study is to compare the interaction profile of Advagraf® and Envarsus® when co-administered with verapamil in healthy subjects and to provide guidelines on tacrolimus dosage adjustment in such cases.

All Clinical Trials for ENVARSUS XR

Trial ID	Title	Status	Sponsor	Phase	Start Date	Summary
NCT02339246 ↗	Pharmacokinetic Comparison Of All FK-506 Formulations	Completed	Veloxis Pharmaceuticals	Phase 3	2015-01-01	The purpose of the study is to compare the pharmacokinetic parameters of three different formulations of tacrolimus. Eligible patients will be treated with all three formulations in a pre-defined sequence.
NCT02411604 ↗	Expanded Access Study for Renal Transplant Patients With Envarsus XR ™	Approved for marketing	Veloxis Pharmaceuticals		1969-12-31	Open label, multi-center, expanded access study for renal transplant patients with once daily Envarsus XR (Tacrolimus).
NCT02432833 ↗	Multicentre, Open Label, Randomized, Two-arm, Parallel-group Study to Assess Efficacy and Safety of ENVARSUS® Compared With Tacrolimus Used as Per Current Clinical Practice in the Initial Maintenance Setting in de Novo Kidney Transplant Patients	Completed	Chiesi Farmaceutici S.p.A.	Phase 4	2015-05-01	The purpose of the study is to compare tacrolimus dosing of the new Envarsus®-based immunosuppressive regimen with current clinical practice (Prograf or Advagraf) over 6 months following de novo renal transplantation in a real-life setting in different European Countries.
NCT02500212 ↗	Pharmacokinetic Study of ENVARSUS in Adult De-novo Kidney Transplant Patients	Completed	Chiesi Farmaceutici S.p.A.	Phase 4	2015-07-01	Open-label, multicentre, randomized clinical trial to compare the pharmacokinetics of ENVARSUS® tablets and ADVAGRAF® capsules administered once daily in adult de-novo kidney transplant patients.
NCT02882828 ↗	PK Assessment of Tacrolimus Exposure Before and After a Switch From Twice Daily Immediate-release (Prograf®) to Once-daily Prolonged Release Tacrolimus (Envarsus®)	Unknown status	University Hospital, Limoges	Phase 4	2016-10-01	Tools have been developed in our unit to calculate the inter-dose AUC (Area Under Curve) of immunosuppressive drugs (ISD) based on a limited number of blood concentrations (i.e., blood samples) using Bayesian methods. Since 2005, we have implemented these tools in an expert system and made them available to the transplant community through our very successful ISBA (Immunosuppressive drugs Bayesian dose Adjustment) website. Briefly, we first need to develop a population pharmacokinetic model using rich pharmacokinetic (PK) profiles (about 10 samples per patient over the dosing interval). The model developed can then be used for inference of ISD PK parameters in new patients using Bayesian estimation. Bayes' theorem is based on conditional probability: individual PK parameters are estimated based on the known PK parameters in the population (mean and distribution), given the dose and concentrations observed in a patient. Our previous studies have shown that a limited sampling strategy (LSS) based on 3 samples collected within the first 3 hours after drug intake can estimate adequately the interdose AUC of ISD. In the present study, the AUC0-24h and the recommended dose will be calculated using Bayesian estimators previously developed using PK data from the clinical trials run by Veloxis, and proposed to the clinicians via a dedicated website comparable with ISBA.
NCT02954198 ↗	Once-daily Regimen With Envarsus® to Optimize Immunosuppression Management and Outcomes in Kidney Transplant Recipients	Completed	Medical University of South Carolina	N/A	2016-12-01	With the availability of well-studied once-daily formulations of tacrolimus, the ability to achieve a true once-daily immunosuppressant regimen along with everolimus and steroids may finally be achievable and have the potential to optimize immunosuppression safety and efficacy in kidney transplantation.
NCT02956005 ↗	Envarsus XR in African American Renal Transplant Recipients	Terminated	Georgetown University	N/A	2016-09-01	The purpose of this study is to collect data prospectively on African American patients who are taking the immunosuppressant Envarsus post kidney transplant. We are looking to see if African American renal transplant recipients that receive Envarsus will have less tubular injury and calcenurin inhibitor toxicity compared with patients that receive tacrolimus IR. African americans have the higher rates of CYP3A5 which is associated with the need of higher tacrolimus dose to achieve an adequate level and this many times is associated with signs and symptoms of tacrolimus toxicity such as tremors, headaches and neuropathies. The retrospective cohort will be African American patients that will be matched by age, gender, type of kidney transplant (living vs deceased) and level of sensitization

Clinical Trial Conditions for ENVARSUS XR

Condition Name

Condition Name for ENVARSUS XR
Intervention	Trials
Immunosuppression	7
Kidney Transplant; Complications	5
Kidney Transplant Failure and Rejection	4
Kidney Transplantation	4

Condition MeSH

Condition MeSH for ENVARSUS XR
Intervention	Trials
Kidney Failure, Chronic	4
Renal Insufficiency	4
Neurotoxicity Syndromes	3
Kidney Diseases	3

Clinical Trial Locations for ENVARSUS XR

Trials by Country

Trials by Country for ENVARSUS XR
Location	Trials
United States	33
France	5
Germany	3
Italy	2
Netherlands	2

Trials by US State

Trials by US State for ENVARSUS XR
Location	Trials
California	4
Tennessee	3
Colorado	3
Wisconsin	2
New York	2

Clinical Trial Progress for ENVARSUS XR

Clinical Trial Phase

Clinical Trial Phase for ENVARSUS XR
Clinical Trial Phase	Trials
PHASE4	3
Phase 4	26
Phase 3	3

Clinical Trial Status

Clinical Trial Status for ENVARSUS XR
Clinical Trial Phase	Trials
Recruiting	22
Not yet recruiting	8
Completed	7

Clinical Trial Sponsors for ENVARSUS XR

Sponsor Name

Sponsor Name for ENVARSUS XR
Sponsor	Trials
Veloxis Pharmaceuticals	22
Chiesi Farmaceutici S.p.A.	4
University of Colorado, Denver	3

Sponsor Type

Sponsor Type for ENVARSUS XR
Sponsor	Trials
Other	63
Industry	28

Envarsus XR (tacrolimus extended-release): Clinical Trials Update, Market Analysis, and Exclusivity-to-Generic Projection

Last updated: July 29, 2026

Executive summary: Envarsus XR (tacrolimus extended-release) is an established, oral once-daily tacrolimus product used to prevent organ rejection in kidney transplant patients. Clinical development has been largely incremental (label expansion and supportive pharmacology/clinical comparability efforts) rather than tied to new active substance IP. From a market view, the category’s near-term growth is driven by continued kidney transplant volumes, uptake among new and stable patients, and substitution dynamics within tacrolimus regimens. Competitive pressure typically comes from generic tacrolimus immediate-release and other extended-release options in markets where exclusivity and patent coverage allow entry. Envarsus XR’s ability to sustain premium pricing depends on where remaining patents cover switching tolerability, extended-release-specific formulations, and dosing regimens, plus any FDA exclusivity attached to the NDA.

What is Envarsus XR and what clinical-trials program is active right now?

Envarsus XR is a tacrolimus extended-release oral product indicated to suppress rejection in kidney transplant patients. The clinical program history is anchored in the NDA-supportive development and then in follow-on studies designed to support broader clinical adoption and practical switching from twice-daily tacrolimus to once-daily extended-release.

Featured snippet:

• Clinical trials for Envarsus XR are primarily supportive and comparative rather than discovery-style new mechanism studies.
• New trial volume in the public domain tends to be geared toward “real-world” switch outcomes (adherence, trough concentration stability, tolerability), and labeling-supportive endpoints.

What endpoints define Envarsus XR studies (and what do they show)?

Common clinical endpoints used across tacrolimus switching and extended-release comparability studies include:

• Incidence of biopsy-confirmed acute rejection (BPAR)
• Tacrolimus trough concentration (C0) attainment and maintenance in target ranges
• Renal function measures (creatinine/eGFR trajectories)
• Safety: nephrotoxicity markers, neurotoxicity, infection, post-transplant metabolic adverse events
• Adherence proxies based on once-daily vs twice-daily regimens

How do tacrolimus exposure targets affect Envarsus XR trial outcomes?

Tacrolimus extended-release dosing strategies focus on stable systemic exposure to reduce trough fluctuations relative to twice-daily regimens. Trial outcomes generally hinge on:

• Proportion of patients achieving and sustaining trough targets
• Rate and magnitude of trough variability during the first months post-conversion
• Dose adjustment burden and time to reach therapeutic troughs

What did Envarsus XR clinical trials recently report on safety, efficacy, and switching?

Recent clinical evidence in this class generally tracks into three practical questions that transplant clinicians and payers care about:

1. Can stable patients switch from twice-daily tacrolimus to Envarsus XR without losing rejection efficacy?
2. Does once-daily dosing improve adherence and real-world stability of tacrolimus levels?
3. Does the safety profile change after conversion, especially around nephrotoxicity risk and infection rates?

Featured snippet:

• Switch studies typically show comparable acute rejection rates and similar or improved trough stability under extended-release exposure management.
• Safety remains driven by the tacrolimus class adverse-event profile, with differences mainly tied to trough variability and patient selection.

Switching from IR tacrolimus to Envarsus XR: what matters clinically?

Clinical practice adoption depends on whether conversion can be managed without:

• Excessive trough subtherapeutic periods (rejection risk)
• Prolonged supratherapeutic exposure (nephrotoxicity risk)

Trial designs usually include dose adjustment protocols and close trough monitoring during conversion windows.

What is the FDA and Orange Book status of Envarsus XR?

Required for exclusivity and generic-projection analysis: The FDA Orange Book and associated patent/exclusivity listings for Envarsus XR determine:

• Patent expiration dates
• Exclusivity protection (e.g., new chemical entity, new molecular entity, pediatric exclusivity)
• Whether any unexpired patents block ANDA submission or force carve-outs/section-specific challenges

Featured snippet:

• Patent and exclusivity status must be verified against the FDA Orange Book for the specific strength and dosage form of Envarsus XR.

What Orange Book listings typically govern Envarsus XR generic entry?

For tacrolimus extended-release products, blocking protections often include:

• Composition-of-matter or formulation patents covering extended-release matrices
• Method-of-use or dosing regimen patents
• Patents specific to stability, release profiles, and manufacturing methods

When does Envarsus XR lose exclusivity, and what patent expirations control generic or biosimilar entry?

Featured snippet:

• Generic risk timing is determined by the latest-to-expire combination of listed Orange Book patents and any FDA-granted exclusivity.

How to project the “first generic” and “durable generic” timelines

A realistic market entry projection for tacrolimus extended-release usually requires mapping:

• Earliest possible ANDA approval date under legal status
• Likely 180-day exclusivity triggers from Paragraph IV filings
• Resolution paths (court decisions, settlements, or stipulations)
• Launch lag from manufacturing scale-up and payer contracting

What would a typical entry scenario look like?

• If there is no patent covering the applicant’s product profile, an ANDA could proceed faster.
• If patents exist, Paragraph IV challenges could lead to either:
  • delayed approval via litigation, or
  • approval on the settlement effective date, or
  • approval with carve-outs (if permitted) where only certain strengths or indications are covered.

Are there Paragraph IV (ANDA) challenges or tacrolimus extended-release litigation affecting Envarsus XR?

Generic entry risk depends on:

• Whether any ANDA applicant filed a Paragraph IV certification against listed patents
• The litigation posture (filed, stayed, dismissed, or decided)
• Whether a settlement triggers an agreed date for market entry

Featured snippet:

• If Paragraph IV litigation exists, it usually dictates both the earliest approval/launch window and market share ramp dynamics.

How do settlements reshape Envarsus XR market projection?

Settlements typically:

• define an entry date (often with a “delayed” but earlier than worst-case timeline),
• restrict launch at the national level for a period, or
• define labeling and manufacturing requirements to avoid “design-around” infringement.

How strong is the patent estate for Envarsus XR and what are the likely claim types protecting it?

Envarsus XR’s patent protection is usually concentrated in:

1. Extended-release formulation IP (matrix, release kinetics, excipient systems)
2. Manufacturing process steps (granulation, compression, controlled release parameters)
3. Methods of treatment that tie pharmacokinetic targets to outcomes (less common than formulation protection, but possible)

Featured snippet:

• For extended-release tacrolimus products, formulation and manufacturing patents generally present the most practical barriers for ANDA design-around.

What patent categories most impact generic launch feasibility?

• Composition and formulation: blocks direct copying without material differences
• Release-profile patents: protect specific extended-release behavior and may be harder to circumvent
• Manufacturing method patents: can raise compliance and infringement risks for an ANDA manufacturer
• Method-of-use patents: can be managed by omitting certain claims, but that depends on FDA labeling and what is deemed infringing in Orange Book terms

What formulations and strengths are protected, and where do generics risk carve-outs?

Envarsus XR is sold in specific strengths, and Orange Book coverage may vary by:

• listed patents covering all strengths or only selected strengths
• formulation or process patents tied to specific release characteristics

Featured snippet:

• Generic entrants often target the easiest-to-approve strength first if only some strengths have the strongest patent coverage.

How does Envarsus XR compare with tacrolimus immediate-release and other extended-release options?

What matters for clinical and payer switching decisions?

• Dosing frequency: once-daily vs twice-daily
• Tacrolimus trough stability and dose-adjustment frequency
• Tolerability and adherence
• Total drug cost after rebate and formulary placement
• Patient subgroup performance: de novo recipients vs stable converters

Commercial impact

When switching is clinically acceptable and managed through monitoring, payers often push for lower-cost alternatives if patent barriers fall away. Until then, branded premium pricing can persist where formularies still favor Envarsus XR.

Market analysis: where Envarsus XR revenue comes from and what drives share

A full market analysis requires exact worldwide and U.S. revenue and volume data. The business logic that drives Envarsus XR performance in transplant formularies is consistent:

Key demand drivers

• Kidney transplant procedure volumes and retransplant rates
• Growth in utilization of tacrolimus-based regimens as standard-of-care
• Switching behavior from IR tacrolimus to extended-release for adherence or pharmacokinetic stability
• Private insurance contracting and Medicare Part D formulary management
• Specialty pharmacy dispensing and patient support programs

Key headwinds

• Patent-driven substitution delays ending in step-changes during generic entry periods
• Payer demand for step edits once lower-cost tacrolimus options are available
• Competition from other immunosuppressants (within transplant rejection prophylaxis regimens)

Revenue projection for Envarsus XR through exclusivity and post-generic entry

A credible projection framework ties:

1. Legal status (Orange Book and exclusivity) to the earliest entry date
2. Litigation or settlement path to a probability-weighted entry window
3. Launch intensity assumptions for generic entrants (single launch vs multiple)
4. Payer switching speed after price compression
5. Patient retention where clinicians prefer the brand

Featured snippet:

• Brand revenue typically holds steady until a legal-to-commercial “window open” date, then declines based on speed of formulary uptake and pharmacy behavior.

Scenario model structure (used for projection)

• Base case: delayed generic entry with slower payer switching due to clinical inertia and monitoring requirements
• Upside case: delayed entry or fewer challengers, sustaining higher price and share
• Downside case: early resolution with multiple entrants and faster step therapy uptake

Geographic projection: where generic substitution may land first

Even when patent expiry occurs in the U.S., commercial substitution timing differs across:

• EU member states and parallel national patent structures
• UK post-Brexit enforcement and local generic launches
• Countries with different regulatory approval timing and patent enforcement mechanisms

Featured snippet:

• Market entry often starts in jurisdictions with clear regulatory pathways and faster enforcement resolution, then expands.

Key takeaways for R&D, licensing, and investment decisions

• Envarsus XR’s clinical evidence base is mature and centered on tacrolimus exposure stability, conversion outcomes, and class safety management rather than new mechanistic differentiation.
• Market upside is anchored to formulary placement and clinician/payer confidence in once-daily tacrolimus stability.
• The revenue and share timeline is driven by the Orange Book patent and exclusivity set for Envarsus XR, plus whether Paragraph IV challenges and settlements trigger an earlier-than-expected launch window.
• Patent estate strength for extended-release tacrolimus products typically concentrates on formulation, release profile, and manufacturing, which raises generic design-around difficulty and slows approval paths.
• Post-entry revenue compression depends on payer switching speed, number of entrants, and availability of therapeutically equivalent tacrolimus extended-release options.

FAQs

1. What clinical endpoints matter most when switching from tacrolimus immediate-release to Envarsus XR?
Trough concentration stability, time-in-range, and rejection rates (BPAR), with safety tied to tacrolimus class adverse events and renal function.

2. How do tacrolimus exposure fluctuations change during conversion to Envarsus XR?
Conversion protocols focus on close therapeutic drug monitoring and dose adjustments to avoid subtherapeutic and supratherapeutic trough periods.

3. What Orange Book patent types most often block generic tacrolimus extended-release products?
Formulation/release profile and manufacturing process patents usually create the highest practical barriers.

4. How do Paragraph IV challenges typically affect when a tacrolimus extended-release generic launches?
They can delay approval via litigation or shift the effective launch date through settlement-triggered dates and stipulations.

5. What payer behaviors accelerate brand-to-generic substitution after legal clearance?
Step therapy, formulary switches at renewal, pharmacy acquisition behavior, and rebate-driven price positioning that encourages dispensing the lowest-cost equivalent.

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References

1. U.S. Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations. (FDA).
2. ClinicalTrials.gov. Studies for tacrolimus extended-release (Envarsus XR) and related tacrolimus formulations. (U.S. National Library of Medicine).