AMBITION trial

Discover the AMBITION trial

AMBITION: A unique PAH trial2-15

Initial combination therapy

  • Evaluated early and aggressive combination therapy with Letairis + tadalafil
  • Different than previous PAH combination trials, which evaluated a sequential add-on treatment approach

Active-control, superiority trial

  • Designed to assess superiority of Letairis + tadalafil vs proven-effective oral monotherapy agents (Letairis or tadalafil alone)

Long-term, event-driven trial

  • Evaluated disease progression, a composite endpoint of the first occurrence of one of the following: death, hospitalization for worsening PAH, short-term clinical worsening, and inadequate long-term clinical response
  • The mean treatment duration was 78.7 weeks

Letairis + tadalafil: A complementary combination16-20

Targets distinct PAH pathways

  • Endothelin pathway:
    • Letairis selectively blocks the ETA* receptor, preventing vasoconstriction and cell proliferation
    • The clinical impact of high selectivity for the ETA receptor is not known
  • Nitric oxide pathway:
    • Tadalafil inhibits PDE-5,† which results in relaxation of pulmonary vascular smooth muscle cells and vasodilation of the pulmonary vascular bed

Simplicity of oral, once-daily dosing

  • Initiate Letairis 5 mg once daily, with or without tadalafil 20 mg once daily. At 4-week intervals, consider either increasing to Letairis 10 mg or tadalafil 40 mg
  • Do not split, crush, or chew tablets
  • Initiate Letairis in females of reproductive potential only after a negative pregnancy test. Obtain monthly pregnancy tests during treatment

No clinically relevant drug-drug interactions exist between Letairis and tadalafil

Extensive market experience

  • Letairis was approved by the FDA in 2007
  • Tadalafil was approved by the FDA for PAH in 2009

*ETA = endothelin type A.
†PDE-5 = phosphodiesterase type 5.

The first and only long-term, event-driven, PAH outcomes trial designed to study the effects of combination therapy with Letairis + tadalafil in treatment-naïve patients with WHO Functional Class (FC) II and III symptoms.2-14

Letairis is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) in combination with tadalafil to reduce the risks of disease progression and hospitalization for worsening PAH, and to improve exercise ability. The study establishing effectiveness included predominantly patients with WHO Functional Class II–III symptoms and etiologies of idiopathic or heritable PAH (58%) or PAH associated with connective tissue diseases (36%).2

Active-controlled trial design2

AMBITION: active-controlled trial design
  • AMBITION: a long-term, event-driven, randomized, double-blind, active-controlled trial in 605 treatment-naïve patients with WHO Functional Class II–III PAH. The mean treatment duration was 78.7 weeks2
  • The study compared combination therapy of Letairis + tadalafil to each of the individual monotherapy arms
  • The primary endpoint was time to first occurrence of (a) death, (b) hospitalization for worsening PAH, (c) >15% decrease from baseline in 6MWD combined with WHO Functional Class III or IV symptoms sustained over 14 days (short-term clinical worsening), or (d) reduction in 6MWD sustained over 14 days combined with WHO Functional Class III or IV symptoms sustained over 6 months (inadequate long-term clinical response)
  • Key secondary endpoints included change from baseline in 6MWD and NT-proBNP at 24 weeks2

Inclusion criteria2

AGE: 18–75 years old WEIGHT: ≥40 kg PAH DIAGNOSIS: idiopathic PAH, heritable PAH, or PAH associated with connective tissue diseases, congenital heart disease, HIV infection, drugs, or toxins WHO FC: II and III symptoms 6MWD: ≥125 m and ≤500 m mPAP: ≥25 mmHg PVR: ≥300 dyn•sec/cm5 PCWP/LVEDP: ≤12 mmHg if PVR ≥300 to 500 dyn•sec/cm5; PCWP/LVEDP ≤15 mmHg if PVR ≥500 dyn•sec/cm5 TLC: ≥60% predicted FEV1: ≥55% predicted SaO2: ≥88% V/Q SCAN: negative

Patient demographics

  • All patients were treatment-naïve2
  • Mean age was 56 years
  • 45% were from North America
  • 76% were female

PAH etiology

55%
43%
3%
  • Idiopathic PAH
  • Heritable PAH
  • APAH

WHO Functional Class

32%
68%
  • WHO FC II
  • WHO FC III

Primary endpoint evaluated disease progression of PAH2

Disease progression is the time to the FIRST occurrence of 1 of the following2:

Hospitalization for worsening PAH

Any PAH hospitalization including:

  • Lung or heart/lung transplant
  • Atrial septostomy
  • Initiation of parenteral prostanoid therapy
OR
Short-term clinical worsening
  • >15% decrease in 6MWD from baseline sustained over 14 days and
  • WHO FC III or IV symptoms sustained over 14 days
OR
Inadequate long-term clinical response
  • Received at least one dose of randomized treatment and enrolled in the study for at least 6 months and
  • Any decrease in 6MWD from baseline sustained over 14 days and
  • WHO FC III or IV symptoms sustained over 6 months
OR
Death (all cause)

Key secondary endpoints (at Week 24)2

  • Change from baseline in 6MWD
  • Change from baseline in NT-proBNP biomarker

View the AMBITION results

View the ARIES trials


Important Safety Information & Indication

BOXED WARNING: EMBRYO-FETAL TOXICITY

  • Do not administer Letairis to a pregnant female because it may cause fetal harm. Letairis is very likely to produce serious birth defects if used by pregnant females, as this effect has been seen consistently when it is administered to animals
  • Exclude pregnancy before the initiation of treatment with Letairis. Females of reproductive potential must use acceptable methods of contraception during treatment with Letairis and for one month after treatment. Obtain monthly pregnancy tests during treatment and 1 month after discontinuation of treatment
  • Because of the risk of embryo-fetal toxicity, females can only receive Letairis through a restricted program called the Letairis REMS program

Contraindications

  • Pregnancy: Letairis can cause fetal harm
  • Idiopathic Pulmonary Fibrosis (IPF), including IPF patients with pulmonary hypertension (WHO Group 3)

Warnings and Precautions

  • Embryo-fetal toxicity and Letairis REMS Program requirements:
    • Prescribers must be certified with the program by enrolling in and completing training
    • All female patients, regardless of reproductive potential, must enroll in the Letairis REMS Program
    • Male patients are not enrolled in the program
    • Pharmacies must be certified with the program and must dispense to female patients who are authorized to receive Letairis

    Further information is available at www.letairisrems.com or 1-866-664-5327.

  • Peripheral edema: Peripheral edema is a known class effect of endothelin receptor antagonists, and is also a clinical consequence of PAH and worsening PAH. Further evaluate patients who develop clinically significant fluid retention to determine the cause and possible need for edema treatment or to discontinue Letairis. In clinical studies, peripheral edema was more common with Letairis than with placebo (most edema was mild to moderate in severity); and with Letairis plus tadalafil than with either drug alone. There have also been postmarketing reports of fluid retention occurring within weeks after starting Letairis that required a diuretic, fluid management, or hospitalization for decompensating heart failure
  • Pulmonary edema with pulmonary veno-occlusive disease (PVOD): Consider PVOD in patients who develop acute pulmonary edema during Letairis initiation and discontinue Letairis if PVOD is confirmed
  • Decreased sperm counts have been observed in patients taking endothelin receptor antagonists and in animal fertility studies with ambrisentan. Counsel patients about potential effects on fertility
  • Hematologic changes: Measure hemoglobin prior to initiation of Letairis, at 1 month, and periodically thereafter. Letairis initiation is not recommended for patients with clinically significant anemia. Consider discontinuing Letairis if clinically significant decreases in hemoglobin occur and other causes have been excluded. Decreases in hemoglobin and hematocrit have been observed within the first few weeks of Letairis treatment, which may persist during treatment. There have also been postmarketing reports of anemia requiring transfusion

Adverse Reactions

  • Most common adverse reactions when used as monotherapy compared to placebo were peripheral edema (17% vs 11%), nasal congestion (6% vs 2%), sinusitis (3% vs 0%) and flushing (4% vs 1%)
  • Most common adverse reactions in combination with tadalafil compared to Letairis or tadalafil monotherapy were peripheral edema (45% vs 38% or 28%), headache (41% vs 34% or 35%), nasal congestion (19% vs 16% or 11%), cough (18% vs 13% or 16%), anemia (15% vs 7% or 11%), dyspepsia (11% vs 3% or 12%), and bronchitis (10% vs 4% or 9%)

Drug Interactions

  • Cyclosporine increases ambrisentan exposure by 2-fold, limit Letairis to 5 mg once daily

Use in Specific Populations

  • Breastfeeding: Choose Letairis or breastfeeding
  • Hepatic impairment: Letairis is not recommended in patients with moderate or severe hepatic impairment. Fully investigate cause of liver injury in patients who develop hepatic impairment; discontinue Letairis if liver aminotransferases are >5x ULN or if elevations are accompanied by bilirubin >2x ULN, or by signs or symptoms of liver dysfunction and other causes are excluded

Dosage and Administration

  • Adult dosage: Initiate Letairis 5 mg once daily, with or without tadalafil 20 mg once daily. At 4-week intervals, consider either increasing to Letairis 10 mg or tadalafil 40 mg. Do not split, crush, or chew tablets
  • Pregnancy testing: Initiate Letairis in females of reproductive potential only after a negative pregnancy test. Obtain monthly pregnancy tests during treatment

INDICATION

Letairis is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise ability and delay clinical worsening; and in combination with tadalafil to reduce the risks of disease progression and hospitalization for worsening PAH, and to improve exercise ability. Studies establishing effectiveness included predominantly patients with WHO Functional Class II–III symptoms and etiologies of idiopathic or heritable PAH (60%) or PAH associated with connective tissue diseases (34%).

Letairis is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) in combination with tadalafil to reduce the risks of disease progression and hospitalization for worsening PAH, and to improve exercise ability. The study establishing effectiveness included predominantly patients with WHO Functional Class II–III symptoms and etiologies of idiopathic or heritable PAH (58%) or PAH associated with connective tissue diseases (36%).1

Letairis is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise ability and delay clinical worsening. Studies establishing effectiveness included predominantly patients with WHO Functional Class II–III symptoms and etiologies of idiopathic or heritable PAH (64%) or PAH associated with connective tissue diseases (32%).

Please click to view full Prescribing Information, including BOXED WARNING.


References: 1. Letairis [package insert]. Foster City, CA: Gilead Sciences, Inc.; November 2018. 2. Data on file. Gilead Sciences, Inc. 3. Galie N, Barbera JA, Frost AE, et al; for the AMBITION investigators. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. N Engl J Med. 2015;373:834-844. 4. Galie N, Brundage BH, Ghofrani HA, et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation. 2009;119:2894-2903. 5. Galie N, Rubin L, Hoeper M, et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. Lancet. 2008;371:2093-2100. 6. Ghofrani HA, Galie N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013;369:330-340. 7. Hoeper MM, Leuchte H, Halank M, et al. Combining inhaled iloprost with bosentan in patients with idiopathic pulmonary arterial hypertension. Eur Respir J. 2006;28:691-694. 8. Humbert M, Barst RJ, Robbins IM, et al. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur Respir J. 2004;24:353-359. 9. McLaughlin VV, Benza RL, Rubin LJ, et al. Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: a randomized controlled clinical trial. J Am Coll Cardiol. 2010;55:1915-1922. 10. McLaughlin VV, Oudiz RJ, Frost A, et al. Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2006;174:1257-1263. 11. Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013;369:809-818. 12. Simonneau G, Rubin LJ, Galie N, et al. Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension: a randomized trial. Ann Intern Med. 2008;149:521-530. 13. Kemp K, Savale L, O'Callaghan DS, et al. Usefulness of first-line combination therapy with epoprostenol and bosentan in pulmonary arterial hypertension: an observational study. J Heart Lung Transplant. 2012;31:150-158. 14. Sitbon O, Jais X, Savale L, et al. Upfront triple combination therapy in pulmonary arterial hypertension: a pilot study. Eur Respir J. 2014;43:1691-1697. 15. McLaughlin VV, Badesch DB, Delcroix M, et al. End points and clinical trial design in pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54(suppl 1):S97-S107. 16. Ghofrani HA, Grimminger F. Modulating cGMP to treat lung diseases. Handb Exp Pharmacol. 2009;191:469-483. 17. Adcirca [Prescribing Information]. Indianapolis, IN: Eli Lilly and Company; April 2015. 18. US Food and Drug Administration website. Drugs@FDA. Available at: http:// www.accessdata.fda.gov/scripts/cder/drugsatfda/. Accessed July 24, 2015. 19. Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med. 2004;351:1425-1436. 20. Ghofrani HA, Humbert M. The role of combination therapy in managing pulmonary arterial hypertension. Eur Respir Rev. 2014;23:469-475.

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