CLINICAL TRIALS PROFILE FOR METHOTREXATE

505(b)(2) Clinical Trials for METHOTREXATE

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	NCT00488475 ↗	Observational Trial With Enbrel	Completed	Pfizer		2006-09-01	The diagnosis, evaluation and treatment of rheumatoid arthritis (RA) continue to undergo rapid change. Randomized controlled trials such as the TEMPO study have demonstrated the efficacy and safety of the combination of etanercept and methotrexate. Importantly, the TEMPO study showed that patients treated with etanercept and methotrexate could reach the newer therapeutic goals of low disease activity and remission, and that the physicians, patients, and payers are no longer prepared to accept the goal of "Reduction of symptoms". RCT are important and powerful tools in assessing efficacy and safety but have their limitations in terms of generalisability. In order to assess health economics, clinical effectiveness and safety of etanercept, they need to be measured by performing observational studies of unselected patients. This study aims to provide a holistic assessment of patients receiving etanercept in a real world setting. This will include centers that would not normally take part in RCT. The study will assess treatment with etanercept with descriptive statistics of the following parameters: Health economic, Safety, Effectiveness. In addition, there was a previous study of similar design, but of only 3 months duration (101354), which will allow comparison with historical data. Since previous study, there have been a number of significant changes: Introduction of a new formulation for etanercept (Enbrel® 50mg · once weekly), Definition of early RA has been modified to short disease duration (from 3 months to 1 year).
New Combination	NCT01643668 ↗	Busulfan/Clofarabine + Allogeneic Stem Cell Transplantation	Completed	Massachusetts General Hospital	Phase 2	2012-07-01	This research is a phase II clinical trial. Phase II clinical trials test the effectiveness of an investigational intervention to learn whether it works in treating a specific cancer. "Investigational" means that the study intervention is still being studied and that research doctors are trying to find out more about it. It also means that the FDA has not yet approved this study intervention for your type of cancer. All participants on this study are treated in an identical manner. The investigators are doing this study because there continues to be a significant risk of relapse of disease after reduced intensity transplantation. In studies which have compared transplants using high-doses of chemotherapy and/or radiation versus reduced intensity transplants, patients undergoing reduced intensity transplants appear to have higher rates of relapse, but lower rates of toxicity and complication. This study attempts to utilize clofarabine, a newer chemotherapy agent shown to be quite active in AML, ALL, and MDS, to increase the anti-tumor effects of the conditioning regimen without accumulating unacceptable toxicity. The reduced intensity allogeneic stem cell transplantation procedure involves giving you chemotherapy in relatively less intense doses to suppress your immune system. This is followed by an infusion of healthy blood stem cells from a matched related donor or a matched unrelated volunteer donor. It is hoped that these donor cells can eventually then attack any cancer cells which remain. In this research study, the investigators are looking to see how well this new combination of busulfan and clofarabine works in reduced intensity allogeneic stem cell transplantation. By "works" the investigators mean to analyze safety, ability of donor cells to engraft (take hold), as well as measures of complications including toxicity, infections, graft-vs-host disease (GVHD), and relapse.
New Dosage	NCT01760226 ↗	Dose Adjusted EPOCH-R, to Treat Mature B Cell Malignancies	Completed	National Cancer Institute (NCI)	Early Phase 1	2013-01-01	The subject is invited to take part in this research study because s/he has been diagnosed with Diffuse Large B-Cell Lymphoma (DLBCL), Primary Mediastinal B-cell Lymphoma (PMBCL), or Post-transplant Lymphoproliferative Disorder (PTLD). In an attempt to improve cure rates while reducing harmful effects from drugs, oncologists are developing new treatment protocols. One such protocol, entitled dose-adjusted EPOCH-R, utilizes two major new strategies. First, the treatment approach utilizes continuous infusion of chemotherapy over four days, instead of being administered over minutes or hours. Secondly, the doses of some medications involved are increased or decreased based on how the drugs affect the subject's ability to produce blood cells, which is used as a measure of how rapidly the body is processing drugs. Using this approach in adults, researchers have shown improved cure rates in these cancers. Additionally, the harmful effects experienced by patients has been mild, with mucositis, severe infections, and tumor lysis syndrome occurring rarely. However, this new dosing method has never been used in children, and the effectiveness and side effects of this new method are unknown in children. The purpose of this study is to look at the safety of dose-adjusted EPOCH-R in the treatment of children with mature B-cell cancers, and to see if we can maintain cure rates (as has been shown in adults). This study represents the first trial of dose-adjusted EPOCH-R in children.
New Dosage	NCT01760226 ↗	Dose Adjusted EPOCH-R, to Treat Mature B Cell Malignancies	Completed	Texas Children's Hospital	Early Phase 1	2013-01-01	The subject is invited to take part in this research study because s/he has been diagnosed with Diffuse Large B-Cell Lymphoma (DLBCL), Primary Mediastinal B-cell Lymphoma (PMBCL), or Post-transplant Lymphoproliferative Disorder (PTLD). In an attempt to improve cure rates while reducing harmful effects from drugs, oncologists are developing new treatment protocols. One such protocol, entitled dose-adjusted EPOCH-R, utilizes two major new strategies. First, the treatment approach utilizes continuous infusion of chemotherapy over four days, instead of being administered over minutes or hours. Secondly, the doses of some medications involved are increased or decreased based on how the drugs affect the subject's ability to produce blood cells, which is used as a measure of how rapidly the body is processing drugs. Using this approach in adults, researchers have shown improved cure rates in these cancers. Additionally, the harmful effects experienced by patients has been mild, with mucositis, severe infections, and tumor lysis syndrome occurring rarely. However, this new dosing method has never been used in children, and the effectiveness and side effects of this new method are unknown in children. The purpose of this study is to look at the safety of dose-adjusted EPOCH-R in the treatment of children with mature B-cell cancers, and to see if we can maintain cure rates (as has been shown in adults). This study represents the first trial of dose-adjusted EPOCH-R in children.
New Dosage	NCT01760226 ↗	Dose Adjusted EPOCH-R, to Treat Mature B Cell Malignancies	Completed	Baylor College of Medicine	Early Phase 1	2013-01-01	The subject is invited to take part in this research study because s/he has been diagnosed with Diffuse Large B-Cell Lymphoma (DLBCL), Primary Mediastinal B-cell Lymphoma (PMBCL), or Post-transplant Lymphoproliferative Disorder (PTLD). In an attempt to improve cure rates while reducing harmful effects from drugs, oncologists are developing new treatment protocols. One such protocol, entitled dose-adjusted EPOCH-R, utilizes two major new strategies. First, the treatment approach utilizes continuous infusion of chemotherapy over four days, instead of being administered over minutes or hours. Secondly, the doses of some medications involved are increased or decreased based on how the drugs affect the subject's ability to produce blood cells, which is used as a measure of how rapidly the body is processing drugs. Using this approach in adults, researchers have shown improved cure rates in these cancers. Additionally, the harmful effects experienced by patients has been mild, with mucositis, severe infections, and tumor lysis syndrome occurring rarely. However, this new dosing method has never been used in children, and the effectiveness and side effects of this new method are unknown in children. The purpose of this study is to look at the safety of dose-adjusted EPOCH-R in the treatment of children with mature B-cell cancers, and to see if we can maintain cure rates (as has been shown in adults). This study represents the first trial of dose-adjusted EPOCH-R in children.

All Clinical Trials for METHOTREXATE

Trial ID	Title	Status	Sponsor	Phase	Start Date	Summary
NCT00000361 ↗	Autoimmunity in Inner Ear Disease	Terminated	National Institute on Deafness and Other Communication Disorders (NIDCD)	Phase 3	1998-03-01	The purpose of this study is to determine whether prednisone, methotrexate, and cyclophosphamide are effective in the treatment of rapidly progressive sensorineural hearing loss in both ears. This condition is called autoimmune inner ear disease (AIED), because it is thought that the hearing loss is triggered by an autoimmune process. Treatment attempts to suppress or control this process with powerful anti-inflammatory drugs. This is a Phase III, outpatient study. All study participants will be assigned to one of four different groups testing the experimental use of drugs. The study is scheduled to run for 18 months, with a minimum of 11 visits per participant.
NCT00000395 ↗	Antifolate Effectiveness in Arthritis	Completed	National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)	Phase 2	1996-09-01	This study looks at how the arthritis drug methotrexate works in low doses to treat rheumatoid arthritis. (High doses of methotrexate are used to treat some types of cancer.) Methotrexate blocks the action of the B-vitamin known as folic acid. We are studying the biochemical reactions affected by this vitamin because we think that blocking many of these reactions may be necessary for methotrexate to work in treating rheumatoid arthritis. Through these studies, we hope to gain a better understanding of how this drug and related drugs work as treatments for arthritis.
NCT00000395 ↗	Antifolate Effectiveness in Arthritis	Completed	Office of Dietary Supplements (ODS)	Phase 2	1996-09-01	This study looks at how the arthritis drug methotrexate works in low doses to treat rheumatoid arthritis. (High doses of methotrexate are used to treat some types of cancer.) Methotrexate blocks the action of the B-vitamin known as folic acid. We are studying the biochemical reactions affected by this vitamin because we think that blocking many of these reactions may be necessary for methotrexate to work in treating rheumatoid arthritis. Through these studies, we hope to gain a better understanding of how this drug and related drugs work as treatments for arthritis.
NCT00000395 ↗	Antifolate Effectiveness in Arthritis	Completed	University of Alabama at Birmingham	Phase 2	1996-09-01	This study looks at how the arthritis drug methotrexate works in low doses to treat rheumatoid arthritis. (High doses of methotrexate are used to treat some types of cancer.) Methotrexate blocks the action of the B-vitamin known as folic acid. We are studying the biochemical reactions affected by this vitamin because we think that blocking many of these reactions may be necessary for methotrexate to work in treating rheumatoid arthritis. Through these studies, we hope to gain a better understanding of how this drug and related drugs work as treatments for arthritis.
NCT00000658 ↗	A Phase III Randomized Trial of Low-Dose Versus Standard-Dose mBACOD Chemotherapy With rGM-CSF for Treatment of AIDS-Associated Non-Hodgkin's Lymphoma	Completed	Schering-Plough	Phase 3	1969-12-31	To determine the impact of dose intensity on tumor response and survival in patients with HIV-associated non-Hodgkin's lymphoma (NHL). HIV-infected patients are at increased risk for developing intermediate and high-grade NHL. While combination chemotherapy for aggressive B-cell NHL in the absence of immunodeficiency is highly effective, the outcome of therapy for patients with AIDS-associated NHL has been disappointing. Treatment is frequently complicated by the occurrence of multiple opportunistic infections, as well as the presence of poor bone marrow reserve, making the administration of standard doses of chemotherapy difficult. A recent study was completed using a low-dose modification of the standard mBACOD (cyclophosphamide, doxorubicin, vincristine, bleomycin, dexamethasone, methotrexate ) treatment. A 46 percent response rate was observed in patients treated with this combination of chemotherapeutic agents, with a number of durable remissions and reduced toxicity when compared to previous experience with more standard treatments. A subsequent study showed similar effectiveness using a lower dose of methotrexate administered on day 15. It is hoped that the use of sargramostim (granulocyte-macrophage colony-stimulating factor; GM-CSF) will improve bone marrow function and allow for administration of a higher dose of chemotherapy.

Clinical Trial Conditions for METHOTREXATE

Condition Name

Condition Name for METHOTREXATE
Intervention	Trials
Rheumatoid Arthritis	497
Leukemia	202
Lymphoma	140
Acute Lymphoblastic Leukemia	96

Condition MeSH

Condition MeSH for METHOTREXATE
Intervention	Trials
Arthritis	653
Arthritis, Rheumatoid	624
Leukemia	442
Lymphoma	324

Clinical Trial Locations for METHOTREXATE

Trials by Country

Trials by Country for METHOTREXATE
Location	Trials
Canada	851
Ukraine	84
Romania	83
Switzerland	82
United States	8,613

Trials by US State

Trials by US State for METHOTREXATE
Location	Trials
Texas	450
California	418
Pennsylvania	349
Florida	338
New York	335

Clinical Trial Progress for METHOTREXATE

Clinical Trial Phase

Clinical Trial Phase for METHOTREXATE
Clinical Trial Phase	Trials
PHASE4	24
PHASE3	16
PHASE2	68

Clinical Trial Status

Clinical Trial Status for METHOTREXATE
Clinical Trial Phase	Trials
Completed	1123
Recruiting	335
Terminated	199

Clinical Trial Sponsors for METHOTREXATE

Sponsor Name

Sponsor Name for METHOTREXATE
Sponsor	Trials
National Cancer Institute (NCI)	340
M.D. Anderson Cancer Center	90
Hoffmann-La Roche	74

Sponsor Type

Sponsor Type for METHOTREXATE
Sponsor	Trials
Other	2404
Industry	1068
NIH	443

Last updated: July 27, 2026

Methotrexate clinical trials update, market analysis and forecast: 2026 exclusivity and competitive landscape

Methotrexate is an off-patent, widely genericized anchor drug used across oncology (choriocarcinoma, osteosarcoma, leukemia), inflammatory disease (rheumatoid arthritis, psoriatic arthritis), and autoimmune indications. No active “drug-specific” exclusivity or proprietary patent estate is meaningfully relevant to market entry for most methotrexate presentations; the market is instead shaped by (1) regulatory substitution across strengths/dosage forms, (2) safety-driven prescriber behavior (monitoring requirements, folate rescue), (3) manufacturing quality and supply continuity, and (4) payer policies and contracting for oral versus parenteral routes.

What matters operationally

• Clinical pipeline activity is concentrated in formulation, route, and supportive-care optimization rather than new active substances.
• Commercial risk is supply- and access-driven, not patent-driven.
• Near-term upside is limited at the molecule level, but can be realized through brand differentiation in formulation, convenience, and market access where specific products are preferred.

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What is the current methotrexate clinical trials landscape and what is changing in 2026?

Featured snippet answer: Methotrexate trials in 2026 are dominated by optimization studies: dosing schedules, route comparisons (oral vs subcutaneous vs intramuscular), therapeutic drug monitoring strategies, and supportive-care regimens that reduce toxicity while maintaining efficacy.

Trial types seen in recent years (and still predominant)

1. Dose and schedule optimization
   • Lower-intensity regimens and modified schedules in chronic inflammatory indications to balance efficacy and tolerability.
2. Route-of-administration comparisons
   • Oral versus subcutaneous methotrexate for adherence, absorption variability, and adverse event mitigation.
3. Safety and monitoring strategies
   • Studies on lab monitoring cadence, renal/hepatic risk stratification, and handling of cytopenias.
4. Combination therapy and sequencing
   • Methotrexate used with biologics or targeted therapies in rheumatology and oncology, focusing on real-world effectiveness and safety.
5. Pharmacokinetic and therapeutic monitoring
   • Increasing use of PK-informed approaches where feasible, especially for higher-dose oncology use.

Where new evidence tends to land

• Rheumatology: adherence, absorption variability, and tolerability in long-term therapy.
• Oncology: supportive care and regimen tolerability, often in combination protocols rather than monotherapy.

(ClinicalTrials.gov and peer-reviewed registries typically show methotrexate as a comparator or background standard rather than a new entity. A drug-level “pipeline update” is therefore mainly a compilation of trials that alter use patterns, not a listing of new mechanism moats.)

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Which methotrexate formulations are getting the most clinical attention: oral, injectable, or high-dose oncology?

Featured snippet answer: Research attention is strongest around oral-to-parenteral transitions (often subcutaneous), reduced-toxicity supportive regimens, and product performance where absorption variability and administration burden drive outcomes.

Oral methotrexate: what trials often target

• Gastrointestinal tolerability.
• Adherence and persistence under weekly dosing.
• Mitigation of malabsorption-related loss of response.

Subcutaneous methotrexate: recurring focus

• Improved bioavailability in patients with inadequate response to oral dosing.
• Reduced injection-site vs systemic tolerability tradeoffs (product-dependent).
• Handling renal impairment with structured monitoring.

High-dose methotrexate in oncology: what changes are tracked

• Leucovorin rescue timing and regimen adjustments.
• Hydration and urine alkalinization protocols and lab thresholds.
• Toxicity management (renal injury, mucositis, cytopenias).

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How strong is the methotrexate patent estate, and when does methotrexate lose exclusivity?

Featured snippet answer: For methotrexate as an active ingredient, the market operates effectively as off-patent. Patent-driven “exclusivity” is generally not a gating factor for generic or biosimilar-like entry because methotrexate is a small molecule with broad generic availability.

What can still be protected even when the molecule is off-patent

• Product-specific formulation patents (rarely decisive at scale for methotrexate).
• Process patents for manufacturing steps (typically not a practical barrier for multiple manufacturers).
• Method-of-use patents for narrow dosing strategies (limited impact because payer and guideline practice tends to revert to established regimens).

Practical implication

• Market entry is usually constrained by FDA approvals, labeling, manufacturing controls, and supply chain capacity, not by waiting out compound exclusivity.

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What patents protect methotrexate products and how many families exist by formulation?

Featured snippet answer: There is no single consolidated, molecule-level proprietary estate that meaningfully limits competition. Patent coverage is mainly scattered across product- or process-specific families, often around controlled-release variants, specific salts, or manufacturing methods.

Patent estate structure seen in small-molecule generics

• Active ingredient patents: expired for decades in most jurisdictions.
• Newer filings: typically incremental improvements, low commercial leverage compared with manufacturing scale and distribution.

Competitive takeaway

• The highest practical differentiator is product execution, not IP.

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What is the Orange Book status of methotrexate: are there any listed patents blocking generics?

Featured snippet answer: Methotrexate is generally represented in the FDA Orange Book by approved ANDAs for multiple strengths and dosage forms with no compound exclusivity that would prevent generic substitution.

How Orange Book typically impacts methotrexate

• For many methotrexate presentations, switching is routine once FDA-approved generics exist.
• Blocking patents, where they exist, are usually product-specific and do not stop market access across the category.

(Note: a current Orange Book pull is required to list specific patent numbers and expiration dates product-by-product. This response is constrained to category-level conclusions.)

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How many Paragraph IV challenges exist for methotrexate, and which generic entrants are most active?

Featured snippet answer: Paragraph IV activity for methotrexate is not a primary market-moving driver at the category level. Any challenges are usually fragmented by presentation and occur on the margin of product-specific exclusivities rather than on the active ingredient.

What drives litigation instead

• Product label disputes that affect switchability.
• Supply and quality incidents.
• Contracting and exclusivity for specific package/strength.

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What methotrexate patent litigation affects the market right now?

Featured snippet answer: Methotrexate category litigation is not typically an ongoing headline driver because the molecule is off-patent and most products compete as generics. Any litigation that impacts market dynamics tends to be localized to specific NDA/ANDA holders and product lifecycle events rather than the methotrexate core.

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Which companies compete for methotrexate market share and how does the competitive landscape look by route?

Featured snippet answer: Competition is broad across:

• Oral methotrexate tablets/capsules: multiple generic manufacturers and distributors compete primarily on contracting, WAC/AMP positioning, and supply continuity.
• Parenteral methotrexate: competition hinges on injection device execution, manufacturability, and lot reliability.

Route-based competitiveness

• Oral: largest volume channel, most substitute options.
• Injectable: fewer SKUs can concentrate share among manufacturers with stable supply.

Commercial reality

• The market is resilient but not high-growth at the molecule level.
• Share shifts are driven by tender wins, pharmacy benefit manager formularies, and shortages.

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What is the methotrexate market size in 2026 and what are the forecast assumptions?

Featured snippet answer: Methotrexate remains a high-volume, low-growth mature drug category globally. Growth is mostly linked to:

• Population-level demand in rheumatology and oncology.
• Shifts in therapy patterns (oral to subcutaneous in selected patients).
• Price compression in generics offset by continued utilization.

Forecast framework for a mature, off-patent molecule

• Volume trend: modest growth with population and guideline adherence.
• Price trend: downward due to generic competition; sometimes stabilized by limited SKU availability in shortages.
• Mix trend: gradual move toward routes that improve adherence and tolerability in chronic disease (context-specific).

(A precise 2026 market size and 2027-2031 forecast requires a dataset source for global revenues by SKU. This response provides the forecast logic rather than an ungrounded numeric projection.)

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How does methotrexate compare with newer rheumatoid arthritis and oncology therapies in cost and adoption?

Featured snippet answer: Methotrexate remains a cost-effective backbone therapy in inflammatory disease and is often the first-line anchor due to guideline positioning, long clinical experience, and low drug cost relative to biologics and targeted agents.

Rheumatology comparison

• Versus biologics/JAK inhibitors: methotrexate has lower drug cost but requires monitoring and has limitations in efficacy for some patients, leading to step-up treatment.
• Adoption pattern: persistent baseline use, with escalation to higher-cost agents in non-responders.

Oncology comparison

• Versus modern regimens: methotrexate is used in multi-agent protocols or disease-specific settings where its efficacy is established and cost is manageable.

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What generic entry risks exist for methotrexate formulations and strengths?

Featured snippet answer: The primary risks are not IP barriers, but manufacturing execution and regulatory approval cycles tied to:

• Strength-specific bioequivalence requirements.
• Injectable product sterility assurance.
• Packaging and device-related stability data.
• Lot-to-lot consistency that affects pharmacy switching confidence.

Where entry friction shows up

• Parenteral formulations with fewer approved options.
• High-dose oncology formats with complex quality and labeling requirements.

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What manufacturing and supply factors could move methotrexate prices or availability in 2026-2027?

Featured snippet answer: Availability shocks, site outages, raw material constraints, and sterile manufacturing capacity are the main levers affecting methotrexate market dynamics.

Supply-side indicators that matter commercially

• Recalls and sterility issues for injectable products.
• Lead-time changes for API intermediates.
• CMS/contracting behavior during shortage periods.
• Distributor allocation policies.

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Key Takeaways

• Methotrexate remains off-patent at the active ingredient level, so exclusivity-driven entry risk is minimal.
• The 2026 clinical update is mainly about optimization: dosing schedules, oral-to-parenteral transition, and toxicity mitigation.
• Market growth is mature and driven by volume/mix, not new proprietary breakthroughs.
• Competitive dynamics are supply and contracting driven, with injectable presentations often more sensitive to manufacturing continuity.
• For business planning, focus on SKU-level availability, payer formularies, and product performance, not on compound-level patent walls.

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FAQs

1. Are there any new methotrexate formulations expected to launch in 2026-2027?
Market activity typically centers on reformulations and manufacturing updates rather than new mechanisms, with launches depending on FDA approval and supply capacity.

2. Does subcutaneous methotrexate have clinical advantages over oral methotrexate?
Clinical practice and trials commonly support improved exposure and tolerability for patients who fail oral regimens, especially when malabsorption is suspected.

3. What safety monitoring requirements most influence methotrexate use in rheumatology?
Renal/hepatic assessment and blood count monitoring, with folate rescue strategies used to reduce toxicity.

4. How do methotrexate shortages impact patient access and payer decisions?
Shortages can drive temporary formulary adjustments, increased use of alternative routes, and tighter contract allocation.

5. What is the most common competitive metric for methotrexate generics?
Contract pricing and reliable distribution of the specific strength and dosage form in demand, with less emphasis on IP-driven product differentiation.

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References

1. U.S. National Library of Medicine. ClinicalTrials.gov. https://clinicaltrials.gov/
2. U.S. Food and Drug Administration. Drugs@FDA. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm
3. U.S. Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm