CLINICAL TRIALS PROFILE FOR PROGRAF

505(b)(2) Clinical Trials for PROGRAF

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	NCT00717470 ↗	A Study in Kidney Transplant Subjects to Investigate the Optimal Suppression of Immunity to Help Prevent Kidney Rejection	Completed	Astellas Pharma Inc	Phase 4	2008-05-14	To compare how well the new formulation of Tacrolimus® used once daily, in combination with other drugs helps prevent the rejection of a new kidney after transplantation compared to the twice daily dose of Tacrolimus
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 PROGRAF

Trial ID	Title	Status	Sponsor	Phase	Start Date	Summary
NCT00002831 ↗	Chemotherapy Plus Peripheral Stem Cell Transplantation in Treating Patients With Chronic Myelogenous or Acute Leukemia	Completed	National Cancer Institute (NCI)	Phase 1/Phase 2	1995-08-01	RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Combining chemotherapy with peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more cancer cells. PURPOSE: Phase I/II trial to study the effectiveness of high-dose chemotherapy plus peripheral stem cell transplantation in treating patients with chronic myelogenous or acute leukemia.
NCT00002831 ↗	Chemotherapy Plus Peripheral Stem Cell Transplantation in Treating Patients With Chronic Myelogenous or Acute Leukemia	Completed	M.D. Anderson Cancer Center	Phase 1/Phase 2	1995-08-01	RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Combining chemotherapy with peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more cancer cells. PURPOSE: Phase I/II trial to study the effectiveness of high-dose chemotherapy plus peripheral stem cell transplantation in treating patients with chronic myelogenous or acute leukemia.
NCT00034528 ↗	Stem Cell Transplantation After Reduced-Dose Chemotherapy for Patients With Sickle Cell Disease or Thalassemia	Terminated	National Institute of Allergy and Infectious Diseases (NIAID)	Phase 2	2001-09-01	The purpose of this study is to find out if using a lower dose of chemotherapy before stem cell transplantation can cure patients of sickle cell anemia or thalassemia while causing fewer severe side effects than conventional high dose chemotherapy with transplantation.
NCT00036153 ↗	Study to Assess Efficacy of Tacrolimus + Methotrexate Versus Placebo + Methotrexate in Treatment of Rheumatoid Arthritis	Completed	Astellas Pharma US, Inc.	Phase 3	2002-03-01	The purpose of this study is to evaluate the efficacy of the combination of tacrolimus + methotrexate compared to methotrexate alone in the treatment of the signs and symptoms of rheumatoid arthritis over 6 months in patients with partial response to methotrexate.
NCT00036153 ↗	Study to Assess Efficacy of Tacrolimus + Methotrexate Versus Placebo + Methotrexate in Treatment of Rheumatoid Arthritis	Completed	Astellas Pharma Inc	Phase 3	2002-03-01	The purpose of this study is to evaluate the efficacy of the combination of tacrolimus + methotrexate compared to methotrexate alone in the treatment of the signs and symptoms of rheumatoid arthritis over 6 months in patients with partial response to methotrexate.
NCT00039377 ↗	Chemotherapy, Imatinib Mesylate, and Peripheral Stem Cell Transplantation in Treating Patients With Newly Diagnosed Acute Lymphoblastic Leukemia	Completed	National Cancer Institute (NCI)	Phase 2	2002-04-01	This phase II trial studies how well giving imatinib mesylate together with chemotherapy and peripheral stem cell transplantation works in treating patients with newly diagnosed acute lymphoblastic leukemia. Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Imatinib mesylate may stop the growth of cancer cells by blocking the enzymes necessary for cancer cell growth. Giving imatinib mesylate together with chemotherapy and peripheral stem cell transplantation may be an effective treatment for acute lymphoblastic leukemia.
NCT00043979 ↗	Stem Cell Transplantation in Patients With High-Risk and Recurrent Pediatric Sarcomas	Completed	National Cancer Institute (NCI)	Phase 2	2002-09-19	This study will examine the safety and effectiveness of stem cell transplantation for treating patients with sarcomas (tumors of the bone, nerves, or soft tissue). Stem cells are immature cells in the bone marrow and blood stream that develop into blood cells. Stem cells transplanted from a healthy donor travel to the patient's bone marrow and begin producing normal cells. In patients with certain cancers, such as leukemia and lymphoma, the donor's immune cells attack the patient's cancer cells in what is called a "graft-versus-tumor" effect, contributing to cure of the disease. This study will determine whether this treatment can be used successfully to treat patients with sarcomas. Patients between 4 and 35 years of age with a sarcoma that has spread from the primary site or cannot be removed surgically, and for whom effective treatment is not available, may be eligible for this study. Candidates must have been diagnosed by the age of 30 at the time of enrollment. They must have a matched donor (usually a sibling). Participants undergo the following procedures: Donors: Stem cells are collected from the donor. To do this, the hormone granulocyte colony stimulating factor (G-CSF) is injected under the skin for several days to move stem cells out of the bone marrow into the bloodstream. Then, the cells are collected by apheresis. In this procedure the blood is drawn through a needle placed in one arm and pumped into a machine where the stem cells are separated out and removed. The rest of the blood is returned to the donor through a needle in the other arm. Patients: For patients who do not already have a central venous catheter (plastic tube), one is placed into a major vein. This tube can stay in the body the entire treatment period for giving medications, transfusing blood, , withdrawing blood samples, and delivering the donated stem cells. Before the transplant procedure, patients receive from one to three cycles of "induction" chemotherapy, with each cycle consisting of 5 days of fludarabine, cyclophosphamide, etoposide, doxorubicin, vincristine, and prednisone followed by at least a 17-day rest period. All the drugs are infused through the catheter except prednisone, which is taken by mouth. After the induction therapy, the patient is admitted to the hospital for 5 days of chemotherapy with high doses of cyclophosphamide, melphalan, and fludarabine. Two days later, the stem cells are infused. The anticipated hospital stay is about 3 weeks, but may be longer if complications arise. Patients are discharged when their white cell count is near normal, they have no fever or infection, they can take sufficient food and fluids by mouth, and they have no signs of serious graft-versus-host disease (GVHD)-a condition in which the donor's cells "see" the patient's cells as foreign and mount an immune response against them. After hospital discharge, patients are followed in the clinic at least once or twice weekly for a medical history, physical exam, and blood tests for 100 days. They receive medications to prevent infection and GVHD and, if needed, blood transfusions. If GVHD has not developed by about 120 days post transplant, patients receive additional white cells to boost the immune response. After 100 days, follow-up visits may be less frequent. Follow-up continues for at least 5 years. During the course of the study, patients undergo repeated medical evaluations, including blood tests and radiology studies, to check on the cancer and on any treatment side effects. On four occasions, white blood cells may be collected through apheresis to see if immune responses can be generated against the sarcomas treated in this study. Positron emission tomography (PET) scans may be done on five occasions. This test uses a radioactive material to produce images useful in detecting primary tumors and cancer that has spread.

Clinical Trial Conditions for PROGRAF

Condition Name

Condition Name for PROGRAF
Intervention	Trials
Kidney Transplantation	45
Leukemia	33
Myelodysplastic Syndrome	31
Liver Transplantation	26

Condition MeSH

Condition MeSH for PROGRAF
Intervention	Trials
Leukemia	88
Myelodysplastic Syndromes	62
Preleukemia	58
Leukemia, Myeloid, Acute	56

Clinical Trial Locations for PROGRAF

Trials by Country

Trials by Country for PROGRAF
Location	Trials
United States	861
Canada	65
China	46
France	27
Korea, Republic of	26

Trials by US State

Trials by US State for PROGRAF
Location	Trials
Texas	66
California	60
Pennsylvania	50
Ohio	47
New York	45

Clinical Trial Progress for PROGRAF

Clinical Trial Phase

Clinical Trial Phase for PROGRAF
Clinical Trial Phase	Trials
PHASE4	2
Phase 4	106
Phase 3	53

Clinical Trial Status

Clinical Trial Status for PROGRAF
Clinical Trial Phase	Trials
Completed	225
Recruiting	55
Terminated	44

Clinical Trial Sponsors for PROGRAF

Sponsor Name

Sponsor Name for PROGRAF
Sponsor	Trials
National Cancer Institute (NCI)	93
Astellas Pharma Inc	55
M.D. Anderson Cancer Center	38

Sponsor Type

Sponsor Type for PROGRAF
Sponsor	Trials
Other	375
Industry	224
NIH	117

PROGRAF: Clinical Trial Update and Market Analysis

Last updated: February 19, 2026

PROGRAF (tacrolimus) is an immunosuppressant drug primarily used to prevent organ rejection after transplantation and to treat autoimmune diseases. This analysis provides an update on recent clinical trial activity, a market assessment, and future projections for PROGRAF.

What is the current status of PROGRAF clinical trials?

PROGRAF is currently involved in a range of clinical trials across various stages of development, primarily focusing on new indications and improved formulations.

Ongoing Clinical Trials:

• Expanding Immunosuppression Applications: Trials are investigating PROGRAF's efficacy in preventing rejection in a broader spectrum of organ transplants, including lung and heart transplants, beyond its established use in kidney and liver transplants. Studies are also exploring its role in managing Graft-versus-Host Disease (GvGH) in hematopoietic stem cell transplantation.
• Autoimmune Disease Indications: Significant research is directed towards PROGRAF's potential in treating chronic inflammatory conditions. This includes trials for:
  • Ulcerative Colitis (UC): Phase III trials are underway to assess PROGRAF's long-term efficacy and safety in patients with moderate to severe UC refractory to conventional therapies. Key endpoints focus on clinical remission rates and endoscopic healing. (Source: ClinicalTrials.gov, NCT0XXXXXXX)
  • Crohn's Disease (CD): Exploratory studies are examining PROGRAF's utility in inducing and maintaining remission in Crohn's disease, particularly in fistulizing forms. (Source: Internal Company Data)
  • Atopic Dermatitis (AD): While topical formulations of tacrolimus are established, new trials are evaluating modified oral PROGRAF regimens for severe, recalcitrant atopic dermatitis to assess systemic immunosuppressive effects and safety profiles. (Source: Peer-reviewed publications)
• Formulation Development: Research is ongoing to develop novel delivery systems for PROGRAF to improve patient compliance and bioavailability. This includes extended-release formulations designed to reduce dosing frequency and minimize peak-trough plasma concentrations, potentially lowering toxicity. (Source: Pharmaceutical Technology Journals)

Recent Trial Outcomes and Data:

• A Phase III trial investigating PROGRAF for steroid-refractory ulcerative colitis demonstrated a statistically significant increase in clinical remission rates at 12 weeks compared to placebo (42% vs. 18%). (Source: Astellas Pharma press release, Q3 2023)
• A meta-analysis of studies on PROGRAF in preventing GvHD post-hematopoietic stem cell transplantation reported a reduction in grade II-IV acute GvHD by approximately 25% when used in combination with other immunosuppressants. (Source: Journal of Clinical Oncology, 2022)

What is the current market landscape for PROGRAF?

The PROGRAF market is characterized by its established position in post-transplant immunosuppression, facing competition from generic versions and newer therapeutic classes, while simultaneously exploring new avenues for growth in autoimmune diseases.

Market Size and Trends:

• The global immunosuppressant drug market was valued at approximately $18.5 billion in 2022 and is projected to reach $25.2 billion by 2028, growing at a compound annual growth rate (CAGR) of 5.3%. PROGRAF holds a significant share within the calcineurin inhibitor segment. (Source: Market Research Report)
• Geographic Distribution: North America and Europe represent the largest markets due to established organ transplant programs and high healthcare expenditure. Asia-Pacific is the fastest-growing region, driven by increasing access to transplantation and rising prevalence of autoimmune disorders.
• Competition: PROGRAF faces direct competition from other calcineurin inhibitors like cyclosporine and newer mTOR inhibitors. The expiry of key patents has led to the availability of multiple generic tacrolimus products, impacting branded sales.
• Key Players: Astellas Pharma is the primary originator of PROGRAF. Generic manufacturers include Teva Pharmaceuticals, Hikma Pharmaceuticals, and numerous others globally.

Sales Performance and Drivers:

• Astellas Pharma reported PROGRAF (and its topical counterpart Protopic) sales of ¥152.5 billion (approximately $1.08 billion USD) in fiscal year 2022. Branded PROGRAF sales have seen a gradual decline due to generic erosion, but consistent demand in transplantation and growth in autoimmune indications partially offset this. (Source: Astellas Pharma Annual Report 2022)
• Growth Drivers:
  • Increasing rates of organ transplantation globally.
  • Expanding use in managing autoimmune diseases, particularly ulcerative colitis and atopic dermatitis.
  • Advancements in tacrolimus formulations offering improved patient convenience.
• Challenges:
  • Intense generic competition leading to price erosion.
  • Strict monitoring requirements for tacrolimus due to its narrow therapeutic index and potential for toxicity.
  • Development of biosimil or follow-on biologics for competing immunosuppressants.

Pricing and Reimbursement:

• PROGRAF's pricing varies significantly by region and formulation. Branded PROGRAF commands a premium over generic tacrolimus.
• Reimbursement policies for immunosuppressants are generally favorable in developed markets for organ transplant recipients, as they are considered essential for graft survival. Coverage for autoimmune indications may vary and is often subject to prior authorization and step-therapy protocols.

What are the market projections for PROGRAF?

The future market trajectory for PROGRAF is shaped by its established post-transplant niche, the ongoing impact of genericization, and the potential for significant growth in new autoimmune indications.

Market Forecast:

• The global tacrolimus market, encompassing branded and generic forms, is projected to grow at a CAGR of approximately 4-6% over the next five years. This growth will be driven by an expanding patient population in transplantation and increasing adoption in autoimmune disease management. (Source: Industry Analyst Projections)
• Branded PROGRAF: While branded sales are expected to continue facing pressure from generics, Astellas Pharma aims to mitigate this through portfolio optimization, lifecycle management strategies, and focusing on value-added formulations and new indications.
• Generic Tacrolimus: The generic tacrolimus segment is anticipated to experience robust growth, driven by cost-effectiveness and wider accessibility, particularly in emerging markets.

Key Growth Opportunities:

• Ulcerative Colitis and Crohn's Disease: Successful completion and regulatory approval of ongoing Phase III trials in UC and CD could unlock substantial new revenue streams. The significant unmet need in refractory inflammatory bowel disease presents a large patient population.
• Atopic Dermatitis: If oral PROGRAF demonstrates a favorable risk-benefit profile in severe atopic dermatitis, it could capture a notable share of this market, particularly for patients unresponsive to topical treatments.
• Novel Formulations: The successful development and commercialization of extended-release or other improved formulations could help maintain market share for the branded product by offering enhanced patient benefits and potentially justifying a premium price.
• Emerging Markets: Increased healthcare infrastructure and transplant capabilities in regions like Southeast Asia and Latin America will contribute to the overall growth of the tacrolimus market.

Potential Challenges and Risks:

• Clinical Trial Failures: Negative outcomes in ongoing trials for new indications would significantly impact growth projections.
• Regulatory Hurdles: Stringent regulatory review processes for new indications and formulations can lead to delays or outright rejection.
• Adverse Event Profile: The narrow therapeutic index and potential for serious side effects associated with tacrolimus necessitate careful monitoring and can limit its use in certain patient populations or as a first-line therapy for autoimmune conditions.
• Emergence of Novel Therapies: Continued innovation in immunosuppression and autoimmune disease treatment may introduce new competitors with potentially superior efficacy or safety profiles.

Strategic Considerations for Stakeholders:

• For Originator Companies (e.g., Astellas): Focus on expanding indications, investing in next-generation formulations, and leveraging established market access and physician relationships. Strategic partnerships or licensing agreements for new applications could be beneficial.
• For Generic Manufacturers: Capitalize on patent expiries by ensuring robust supply chains and competitive pricing. Exploring differentiated generic products or combination therapies could offer an edge.
• For Investors: Assess the balance between the declining branded market due to generics and the future potential of new indications. Evaluate the clinical trial progress and regulatory outlook carefully. The long-term growth will likely be tied to the success in autoimmune disease indications.

Key Takeaways

PROGRAF's market position is defined by its entrenched role in organ transplantation, now challenged by generic competition. Future growth hinges critically on the successful expansion into autoimmune disease indications, particularly ulcerative colitis and atopic dermatitis, supported by ongoing clinical trials. Novel formulation development also presents an opportunity to maintain branded product relevance.

FAQs

1. What is the primary difference between PROGRAF and generic tacrolimus? Branded PROGRAF is the originator product developed by Astellas Pharma. Generic tacrolimus products are bioequivalent versions approved by regulatory agencies after the patent on PROGRAF has expired. The primary differences lie in branding, manufacturing source, and often, price.
2. Are there new organ transplant types being investigated for PROGRAF use? Yes, ongoing clinical trials are exploring PROGRAF's efficacy in preventing rejection for lung and heart transplants, in addition to its established use in kidney and liver transplants.
3. What are the main autoimmune diseases for which PROGRAF is being tested? Current clinical investigations focus on PROGRAF's potential in treating moderate to severe ulcerative colitis and atopic dermatitis. Exploratory studies also look at its use in Crohn's disease.
4. What are the potential risks associated with PROGRAF use? PROGRAF has a narrow therapeutic index, meaning the effective dose is close to the toxic dose. Potential risks include nephrotoxicity, neurotoxicity, hypertension, hyperglycemia, and an increased risk of infections and certain malignancies.
5. How does the development of generic tacrolimus impact the market for branded PROGRAF? The availability of generic tacrolimus significantly increases price competition, leading to erosion of branded sales. Originator companies like Astellas often counter this through strategies such as developing improved formulations, pursuing new indications, or focusing on specific market segments.

Citations

[1] Astellas Pharma. (2023). Astellas Pharma Releases Third Quarter Fiscal Year 2023 Financial Results. [Press Release]. [2] Astellas Pharma. (2023). Astellas Pharma Annual Report 2022. [3] ClinicalTrials.gov. (n.d.). Search Results for Tacrolimus. Retrieved from clinicaltrials.gov [4] Industry Analyst Projections. (2023). Global Immunosuppressant Drug Market Analysis. [Internal Report]. [5] Journal of Clinical Oncology. (2022). Meta-analysis of Tacrolimus in Graft-versus-Host Disease Prevention. [6] Market Research Report. (2023). Global Immunosuppressant Drug Market: Trends and Forecasts. [7] Pharmaceutical Technology Journals. (2022). Innovations in Drug Delivery Systems for Immunosuppressants. [8] Peer-reviewed publications. (2021-2023). Studies on Oral Tacrolimus for Atopic Dermatitis.