CLINICAL TRIALS PROFILE FOR AMBRISENTAN

505(b)(2) Clinical Trials for AMBRISENTAN

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	NCT02688387 ↗	A Phase 1 Relative Bioavailability Study of Ambrisentan and Tadalfil Fixed Dose Combination Tablets in Healthy Subjects	Completed	Covance Harrogate	Phase 1	2016-03-18	This study is designed to understand the relative bioavailability (proportion of the administered dose that is absorbed into the bloodstream) of several fixed dose combinations (FDCs) tablets of ambrisentan and tadalafil for further development and to provide pharmacokinetic (PK - what the body does to the drug) data to enable a pivotal bioequivalence (BE - the relationship between two preparations of the same drug in the same dosage form that have a similar bioavailability) study. Depending on formulation work, the study will allow up to 8 new FDCs to be compared with the reference of ambrisentan and tadalafil monotherapies. The study will also evaluate up to 2 of the new formulations, that may be taken in to a BE study, to be tested for any effect on pharmacokinetics of the FDC in both fed and fasted state. This is a single centre, Phase 1, single dose, randomised, open label crossover study with 3 study parts; each study part will have up to a 5 way crossover in healthy subjects. Part 1 of the study will evaluate four formulations of the FDC (ambrisentan 10 milligram [mg] + tadalafil 40 mg) and the reference of the 2 monotherapy components taken concurrently (ambrisentan 10 mg and tadalafil 40 mg) in the fasted stated. If successful formulations are identified in this part of the study, then they will be re-formulated and tested in part 2. If no successful formulations are identified in part 1 of the study, then part 2 will be utilized to look at up to 4 new FDC formulations. However, if only two formulations, or less, are evaluated in part 2 then the FDC formulations may be tested both fed and fasted to assess food effect and part 3 will not be required. If successful formulations are identified in this study part, then up to 2 of these may be tested, for food effect, in Part 3 if not already assessed in this part. Therefore, part 3 is optional and utility is dependent on the results of the previous study parts.
New Formulation	NCT02688387 ↗	A Phase 1 Relative Bioavailability Study of Ambrisentan and Tadalfil Fixed Dose Combination Tablets in Healthy Subjects	Completed	Hammersmith Medicines Research	Phase 1	2016-03-18	This study is designed to understand the relative bioavailability (proportion of the administered dose that is absorbed into the bloodstream) of several fixed dose combinations (FDCs) tablets of ambrisentan and tadalafil for further development and to provide pharmacokinetic (PK - what the body does to the drug) data to enable a pivotal bioequivalence (BE - the relationship between two preparations of the same drug in the same dosage form that have a similar bioavailability) study. Depending on formulation work, the study will allow up to 8 new FDCs to be compared with the reference of ambrisentan and tadalafil monotherapies. The study will also evaluate up to 2 of the new formulations, that may be taken in to a BE study, to be tested for any effect on pharmacokinetics of the FDC in both fed and fasted state. This is a single centre, Phase 1, single dose, randomised, open label crossover study with 3 study parts; each study part will have up to a 5 way crossover in healthy subjects. Part 1 of the study will evaluate four formulations of the FDC (ambrisentan 10 milligram [mg] + tadalafil 40 mg) and the reference of the 2 monotherapy components taken concurrently (ambrisentan 10 mg and tadalafil 40 mg) in the fasted stated. If successful formulations are identified in this part of the study, then they will be re-formulated and tested in part 2. If no successful formulations are identified in part 1 of the study, then part 2 will be utilized to look at up to 4 new FDC formulations. However, if only two formulations, or less, are evaluated in part 2 then the FDC formulations may be tested both fed and fasted to assess food effect and part 3 will not be required. If successful formulations are identified in this study part, then up to 2 of these may be tested, for food effect, in Part 3 if not already assessed in this part. Therefore, part 3 is optional and utility is dependent on the results of the previous study parts.
New Formulation	NCT02688387 ↗	A Phase 1 Relative Bioavailability Study of Ambrisentan and Tadalfil Fixed Dose Combination Tablets in Healthy Subjects	Completed	GlaxoSmithKline	Phase 1	2016-03-18	This study is designed to understand the relative bioavailability (proportion of the administered dose that is absorbed into the bloodstream) of several fixed dose combinations (FDCs) tablets of ambrisentan and tadalafil for further development and to provide pharmacokinetic (PK - what the body does to the drug) data to enable a pivotal bioequivalence (BE - the relationship between two preparations of the same drug in the same dosage form that have a similar bioavailability) study. Depending on formulation work, the study will allow up to 8 new FDCs to be compared with the reference of ambrisentan and tadalafil monotherapies. The study will also evaluate up to 2 of the new formulations, that may be taken in to a BE study, to be tested for any effect on pharmacokinetics of the FDC in both fed and fasted state. This is a single centre, Phase 1, single dose, randomised, open label crossover study with 3 study parts; each study part will have up to a 5 way crossover in healthy subjects. Part 1 of the study will evaluate four formulations of the FDC (ambrisentan 10 milligram [mg] + tadalafil 40 mg) and the reference of the 2 monotherapy components taken concurrently (ambrisentan 10 mg and tadalafil 40 mg) in the fasted stated. If successful formulations are identified in this part of the study, then they will be re-formulated and tested in part 2. If no successful formulations are identified in part 1 of the study, then part 2 will be utilized to look at up to 4 new FDC formulations. However, if only two formulations, or less, are evaluated in part 2 then the FDC formulations may be tested both fed and fasted to assess food effect and part 3 will not be required. If successful formulations are identified in this study part, then up to 2 of these may be tested, for food effect, in Part 3 if not already assessed in this part. Therefore, part 3 is optional and utility is dependent on the results of the previous study parts.

All Clinical Trials for AMBRISENTAN

Trial ID	Title	Status	Sponsor	Phase	Start Date	Summary
NCT00091598 ↗	ARIES - Ambrisentan in Patients With Moderate to Severe Pulmonary Arterial Hypertension (PAH)	Completed	Gilead Sciences	Phase 3	2004-01-01	The primary objective is to determine the effect of ambrisentan on exercise capacity in subjects with PAH.
NCT00380068 ↗	Safety and Efficacy Study of Ambrisentan in Subjects With Pulmonary Hypertension	Completed	Gilead Sciences	Phase 3	2006-08-01	The primary objective of this study was to evaluate the safety and efficacy of ambrisentan in a broad population of participants with pulmonary hypertension (PH). Secondary objectives of this study were to evaluate the effects of ambrisentan on other clinical measures of pulmonary arterial hypertension (PAH), long-term treatment success, and survival.
NCT00423202 ↗	A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Assess Safety and Efficacy of Ambrisentan in Subjects With Pulmonary Arterial Hypertension.	Completed	Gilead Sciences	Phase 3	2003-12-01	A phase 3, randomized, double-blind, placebo-controlled study to assess safety and efficacy of ambrisentan in subjects with pulmonary arterial hypertension.
NCT00423592 ↗	Phase 2 Study of Ambrisentan for Liver Function Test Rescue in Pulmonary Arterial Hypertension	Completed	Gilead Sciences	Phase 2	2005-05-01	This Phase 2 study was to determine the incidence of increased serum aminotransferase concentrations (alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST]), as well as the overall safety and tolerability of ambrisentan, in participants with pulmonary arterial hypertension (PAH), idiopathic PAH (IPAH), or familial PAH (FPAH) who had previously discontinued ERA therapy (bosentan or sitaxsentan) due to increased serum ALT or AST concentrations.
NCT00423748 ↗	Study to Assess Safety and Efficacy of Ambrisentan in Subjects With Pulmonary Arterial Hypertension.	Completed	Gilead Sciences	Phase 3	2003-12-01	A phase 3, randomized, double-blind, placebo-controlled study to assess safety and efficacy of ambrisentan in subjects with pulmonary arterial hypertension.
NCT00424021 ↗	Phase 2 Extension Study of Ambrisentan in Pulmonary Arterial Hypertension	Completed	Gilead Sciences	Phase 2	2003-04-01	AMB-220-E is an international, multicenter, open-label study examining the long-term safety of ambrisentan (BSF 208075) in subjects who have previously completed Myogen study NCT00046319, "A Phase II, Randomized, Double-Blind, Dose-Controlled, Dose-Ranging, Multicenter Study of BSF 208075 Evaluating Exercise Capacity in Subjects with Moderate to Severe Pulmonary Arterial Hypertension".

Clinical Trial Conditions for AMBRISENTAN

Condition Name

Condition Name for AMBRISENTAN
Intervention	Trials
Pulmonary Arterial Hypertension	17
Pulmonary Hypertension	15
Hypertension, Pulmonary	8
Systemic Sclerosis	5

Condition MeSH

Condition MeSH for AMBRISENTAN
Intervention	Trials
Hypertension	45
Pulmonary Arterial Hypertension	33
Hypertension, Pulmonary	29
Familial Primary Pulmonary Hypertension	28

Clinical Trial Locations for AMBRISENTAN

Trials by Country

Trials by Country for AMBRISENTAN
Location	Trials
United States	229
Germany	42
Canada	34
Spain	23
Australia	22

Trials by US State

Trials by US State for AMBRISENTAN
Location	Trials
Massachusetts	14
California	13
North Carolina	11
Texas	11
Pennsylvania	10

Clinical Trial Progress for AMBRISENTAN

Clinical Trial Phase

Clinical Trial Phase for AMBRISENTAN
Clinical Trial Phase	Trials
PHASE4	1
PHASE3	1
PHASE2	1

Clinical Trial Status

Clinical Trial Status for AMBRISENTAN
Clinical Trial Phase	Trials
Completed	39
Terminated	11
Recruiting	8

Clinical Trial Sponsors for AMBRISENTAN

Sponsor Name

Sponsor Name for AMBRISENTAN
Sponsor	Trials
Gilead Sciences	22
GlaxoSmithKline	13
Noorik Biopharmaceuticals AG	3

Sponsor Type

Sponsor Type for AMBRISENTAN
Sponsor	Trials
Other	108
Industry	48
NIH	4

Ambrisentan (Letairis) Clinical Trials Update and Market Outlook

Last updated: April 25, 2026

What is ambrisentan and what approvals define its commercial scope?

Ambrisentan is an endothelin receptor antagonist (ERA) approved for pulmonary arterial hypertension (PAH). The marketed indication set is anchored by United States approvals and mirrored in major markets via labeling that follows the PAH treatment framework.

Core approved use (U.S.)

• PAH (WHO Group 1), to improve exercise capacity and delay clinical worsening in adults with:
  • NYHA functional class II, III, or IV
• It is used as part of PAH therapy patterns (often in combination with other agents such as PDE5 inhibitors) but the label basis is ER inhibition for PAH symptom and progression control.

Representative commercial product

• Letairis (ambrisentan), by Gilead (labeling history varies by jurisdiction, but Letairis is the principal branded reference in major markets).

Primary references

• FDA label and clinical data are the controlling documentation for approved dosing and efficacy endpoints. (See [1] for U.S. prescribing information.)

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What is the clinical-trials status: active programs, readouts, and the latest evidence base?

Ambrisentan’s late-stage clinical base is mature and anchored in pivotal PAH efficacy trials and long-term safety exposure. As a result, the current “update” is best expressed as (1) post-approval evidence continuity and (2) ongoing or derivative studies that extend use into treatment strategies, special populations, dosing regimens, and real-world evidence.

How is evidence typically updated in PAH ERAs like ambrisentan?

Clinical update pathways for ambrisentan generally fall into three buckets:

1. Combination strategy trials (ambrisentan with PDE5 inhibitors or other PAH agents), focused on functional class improvements and clinical worsening delays.
2. Long-term extension safety and registries to characterize hepatotoxicity, edema, anemia, pregnancy risk controls, and durability of efficacy.
3. Real-world and health-economic analyses derived from claims/registry data to estimate time on therapy, adherence, discontinuation, and downstream outcomes.

Most current public-facing “update” sources

• FDA label evidence remains the anchor for dosing, boxed warnings, and the pivotal efficacy findings that define the marketed claims. (See [1].)
• ClinicalTrials.gov is the primary cross-company registry for any ongoing trials and planned updates. (See [2].)
• EMA public assessment and SmPC (where accessible) provides regulatory harmonization and post-approval wording. (See [3].)

Key trial evidence that still drives clinical use

Even when new studies appear, ambrisentan’s clinical position rests on PAH endpoints such as:

• 6-minute walk distance (6MWD) or exercise capacity improvements
• Time to clinical worsening
• Hemodynamics and biomarkers in subset analyses
• Safety including liver enzyme elevations, anemia risk, edema, and pregnancy-related teratogenicity controls

Regulatory safety controls remain central

• Boxed warning for embryo-fetal toxicity with strict pregnancy prevention measures.
• Monthly pregnancy testing requirements for patients of childbearing potential (U.S. label).
• Liver enzyme monitoring based on label instructions and clinical management algorithms. (See [1].)

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What is the competitive and clinical landscape: where does ambrisentan sit versus other PAH ERAs?

Ambrisentan competes in the endothelin pathway segment against:

• Bosentan (ERA, older class member)
• Macitentan (ERA with broader convenience and outcome data in clinical development history)

Why ambrisentan’s differentiation matters commercially

Ambrisentan’s value proposition in the market typically centers on:

• Established PAH efficacy positioning with long commercial history
• Treatment line inclusion for NYHA II-III and broader PAH management strategies
• Safety profile that is managed through standardized monitoring and pregnancy prevention systems

In contrast, macitentan is often preferred where prescribers prioritize outcome endpoints and dosing convenience; bosentan has other adoption dynamics based on dosing frequency and monitoring burden.

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How big is the PAH market the drug participates in, and what share does ERA therapy command?

Ambrisentan revenue is downstream of the PAH treated-population size and the proportion of patients receiving endothelin receptor antagonists. The PAH market is concentrated in:

• Major EU5 and U.S.
• Specialty centers with high adherence to guideline-based PAH sequencing.

Market sizing logic used by investors and commercial planners

A practical market model usually maps:

1. Incident and prevalent PAH patient pools in covered geographies
2. Treatment penetration into disease-modifying regimens (ERAs, PDE5 inhibitors, sGC stimulators, prostacyclin pathway agents)
3. Sequencing and switching rates due to clinical worsening, intolerance, payer restrictions, and pregnancy-related contraindications
4. Net price realization after rebates and patient-access agreements

In mature products like ambrisentan, most “projection lift” comes less from clinical trial breakthroughs and more from:

• Country-level pricing changes
• Patent and genericization timing
• Patient switching among ERAs
• Uptake within guideline-based combination therapy

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What are the patent and exclusivity signals that drive pricing and unit-cost risk?

For ambrisentan, exclusivity and patent expiry timelines across jurisdictions historically shape:

• Entry of generics/biosimilars-like dynamics for small-molecule products (direct generic substitution)
• Loss of brand premium and shift to lower-cost supply
• Manufacturer switching based on payer formularies

The key commercial risk for mature PAH assets is not “trial outcome” but loss of exclusivity and formulary erosion.

Regulatory labeling remains stable even as price declines accelerate post-generic entry. The FDA and EMA documents define safety controls and dosing, which do not prevent generic substitution once legal status allows. (See [1], [3].)

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What is the near-term commercial trajectory: unit demand, price, and substitution dynamics?

Because ambrisentan is an older ERA in a chronic disease, the near-term revenue outlook is driven by:

1) Unit demand stability

• PAH is a progressive condition with ongoing treatment needs.
• Disease-modifying therapy reduces clinical worsening time but does not “cure,” so baseline demand persists.

2) Net price compression

• Generic entry reduces price realization.
• Even without full generic substitution, payers frequently tier alternatives within the ERA class.

3) Switching between ERAs

• Physicians may switch among ERAs based on tolerability, edema/anemia, lab monitoring adherence, and perceived efficacy.
• Payers influence switching through step edits and preferred formulary status.

4) Pregnancy prevention regimen impact

• The boxed warning and mandatory pregnancy testing standardize risk management; this can constrain utilization in real-world subpopulations where risk tolerance and monitoring access differ. (See [1].)

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Market projection: base case, downside, and upside by scenario

The model below is structured for business decision-making: it is explicit about what changes revenue.

Assumptions that typically move the needle for ambrisentan

• Brand erosion pace (generic penetration and payer switching)
• Therapy mix shifts within ERAs (macitentan preference versus bosentan and ambrisentan)
• PAH treated population growth (diagnosis rates, referral patterns, and survival)
• Rebate and net price movement (U.S. and EU)

Scenario table (directional, decision-grade)

Driver	Upside scenario	Base case	Downside scenario
ERA formulary position	Sustained payer preference	Neutral-to-declining preference	Rapid tier demotion to preferred ERAs
Net price	Slower price compression	Continued compression	Faster generic substitution and deeper rebates
Treated population	Higher diagnosis and longer survival	Stable growth	Flat or slower growth due to access constraints
Switching	Lower switching out of ambrisentan	Moderate switching	High switching to alternative ERAs

What this means for revenue shape

• In a mature ERA, the expected revenue curve is usually downward unless there is an interruption in generic penetration, a payer reversal, or a special patient subset where ambrisentan remains preferred.

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What is the investment-relevant “watch list” for clinical and regulatory catalysts?

For ambrisentan specifically, catalysts tend to be:

• Any new phase 3 or phase 4 readouts that create guideline movement or improve endpoints versus competitors
• Any label expansion with new PAH subpopulations or dosing schedules (rare for this late-stage asset)
• Any safety signal updates that could change monitoring requirements and payer comfort

The FDA label and EMA SmPC represent the controlling baseline for safety and usage language. (See [1], [3].)

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Key Takeaways

• Ambrisentan is a mature ERA for PAH with U.S. labeling that anchors use in adult NYHA functional classes II to IV and is tied to strict pregnancy prevention and monitoring requirements. (See [1].)
• Clinical update momentum is incremental: most “updates” come through post-approval evidence and strategy use, not new label-defining efficacy breakthroughs.
• Market projections hinge on pricing and formulary dynamics more than on incremental clinical efficacy; generic substitution and ERA class switching are the dominant revenue variables.
• The controlling commercial risk is exclusivity and payer tiering, which determines net price trajectory and uptake within combination regimens.

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FAQs

1) Is ambrisentan a first-line therapy in PAH?

It is used as a foundational disease-modifying PAH therapy within guideline-based sequencing, commonly in combination regimens, with labeling covering multiple NYHA classes. (See [1].)

2) What safety controls are mandatory for prescribing ambrisentan?

U.S. labeling requires strict pregnancy prevention measures, monthly pregnancy testing for patients of childbearing potential, and liver monitoring per label instructions. (See [1].)

3) What are the main clinical endpoints that define ambrisentan efficacy?

PAH efficacy evidence centers on exercise capacity and time to clinical worsening, supported by hemodynamic and biomarker assessments in supporting analyses. (See [1].)

4) Who are the key competitors in the ERA market?

The principal ERA comparators are bosentan and macitentan, with frequent payer-led formulary comparisons and physician switching among endothelin pathway agents.

5) What drives revenue for a mature PAH ERA like ambrisentan?

Net price realization after generic penetration, ERA formulary status, and patient switching between ERAs typically drive revenue more than new trial readouts.

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References

[1] U.S. Food and Drug Administration. (n.d.). Letairis (ambrisentan) prescribing information. FDA.
[2] U.S. National Library of Medicine. (n.d.). ClinicalTrials.gov: Ambrisentan studies.
[3] European Medicines Agency. (n.d.). Assessment history and product information for ambrisentan. EMA.