Ambrisentan is an ETA selective receptor antagonist being developed as an oral therapy for patients with pulmonary arterial hypertension.
Ambrisentan is member of a class of therapeutic agents known as endothelin receptor antagonists, or ERAs, that can be orally administered. Endothelin is a small peptide hormone that is believed to play a critical role in the control of blood flow and cell growth. Elevated endothelin blood levels are associated with several cardiovascular disease conditions, including PAH. Therefore, many scientists believe that agents that block the detrimental effects of endothelin will provide significant benefits in the treatment of these conditions. There are two classes of endothelin receptors, ETA and ETB, which play significantly different roles in regulating blood vessel diameter. The binding of endothelin to ETA receptors located on smooth muscle cells causes vasoconstriction, or narrowing of the blood vessels. However, the binding of endothelin to ETB receptors located on the vascular endothelium causes vasodilation through the production of nitric oxide and prostacyclin. The activity of the ETB receptor is thought to be counter-regulatory, protecting against excessive vasoconstriction.
We believe that a significant opportunity exists for a new class of ERAs that bind selectively to the ETA receptor in preference to the ETB receptor. Selective ETA antagonists are likely to block the negative effects of endothelin by preventing the harmful effects of vasoconstriction and cell proliferation, while preserving the beneficial effects of the ETB receptor. We believe that the potential clinical benefits of selective ETA antagonists will position these compounds as the treatment of choice for PAH, resistant systolic hypertension and potentially other cardiovascular disorders.
Ambrisentan is an ERA that is selective for the ETA receptor. The compound demonstrates high potency, high bioavailability and half-lives that we believe are suitable for once daily dosing. In addition, the compounds do not induce or inhibit the p450 metabolic pathway. We believe the selectivity and potency of our ERAs may offer significant advantages over other ERAs, including enhanced and more durable efficacy, safety and ease of use (alone or in combination with other therapies). We have initially chosen to evaluate ambrisentan in PAH.
Ambrisentan is being developed as an oral therapy for patients with PAH. We completed a Phase 2 clinical trial of ambrisentan in September 2003 and we initiated two pivotal Phase 3 clinical trials (ARIES 1 & 2) for this condition in January 2004. Enrollment in ARIES-2 was completed in August 2005 and top line results were reported on December 12, 2005. Enrollment in ARIES-1 was completed in November 2005 and we expect to report top line results in the second quarter of 2006.
Ambrisentan has been granted orphan drug designation for the treatment of PAH in both the United States and Europe.
Therapeutic Opportunity
Pulmonary arterial hypertension is a highly debilitating disease characterized by severe constriction of the blood vessels in the lungs leading to very high pulmonary arterial pressures. These high pressures make it difficult for the heart to pump blood through the lungs to be oxygenated. Pulmonary arterial hypertension can occur with no known underlying cause, or it can occur secondary to diseases like scleroderma (an autoimmune disease of the connective tissues), cirrhosis of the liver, congenital heart defects and HIV infection. Patients with PAH suffer from extreme shortness of breath as the heart struggles to pump against these high pressures causing such patients to ultimately die of heart failure. Pulmonary arterial hypertension afflicts approximately 200,000 patients worldwide.
Mild to moderate PAH is currently treated with calcium channel blockers, diuretics and anticoagulants. As patients advance into more severe stages of disease, moderate to severe PAH, therapeutic options become more limited. Prior to 2001, only continuous intravenous infusion of prostacyclin, epoprostenol (Flolan(R)), was available as a treatment for patients with more advanced stages of PAH. In mid-2002, a more stable form of prostacyclin that can be administered via continuous subcutaneous infusion, treprostinil (Remodulin(R)), was approved by the FDA. In late 2004, the FDA approved an intravenous formulation of treprostinil and in December 2004 the FDA approved iloprost (Ventavis(R)), an inhaled form of prostacyclin.
The most significant therapeutic advance for patients with moderate to severe PAH took place in December 2001 with the approval of a twice-a-day oral formulation of bosentan (Tracleer(R)), a non-selective ERA. Bosentan was demonstrated in clinical trials to improve exercise capacity and quality of life and has now become first line therapy for patients with Class III PAH. In November 2004, Pfizer Inc. completed clinical trials for sildenafil (Viagra(R)) for the treatment of PAH and reported results of the trial at the annual conference of the American College of Chest Physicians in October 2004. The results of this study suggest that sildenafil could become a major competitor to ambrisentan and other PAH products.
In February 2005, Encysive Pharmaceuticals, Inc. announced preliminary results of its pivotal Phase III trial (STRIDE-2) of sitaxsentan (Thelin(TM)) for PAH. Like ambrisentan, sitaxsentan is an ETA receptor selective antagonist compound. The preliminary results of the STRIDE-2 trial suggest that sitaxsentan could also become a major competitor to ambrisentan and other PAH products.
We believe that ambrisentan could have several clinical benefits over existing therapies and other ERAs under development, including:
greater and more durable efficacy;
low incidence of liver toxicity that does not appear to be dose related;
high potency and bioavailability allowing low doses for therapeutic effect;
multiple dose options;
once daily dosing based on its half-life; and
lower incidence of interactions with other drugs, including anticoagulants and sildenafil.
Overview of Phase 2 Clinical Results
In September 2003, we completed a randomized, double-blind, multi-center, dose-ranging Phase 2 study evaluating the effect of ambrisentan on exercise capacity of patients with moderate to severe PAH. Exercise capacity was the primary efficacy endpoint and was measured as the change from baseline in the six-minute walk test distance after 12 weeks of treatment. The secondary endpoints were Borg Dyspnea Index, Patient Global Assessment, time to clinical worsening and World Health Organization, or WHO, Functional Class, which are tests used by physicians to assess the severity of PAH. Right heart and pulmonary artery hemodynamics (blood pressures and blood flow in the heart and lungs) were evaluated in a subset of patients.
A total of 64 patients were randomized to one of four ambrisentan dose groups (1.0, 2.5, 5.0 or 10.0 milligrams). Doses were administered orally once a day for 12 weeks. After 12 weeks of treatment, patients were allowed to enter an optional 12-week open-label extension period of the study where dose adjustment was allowed. This open-label extension study was followed by an optional long-term open-label safety study that is ongoing. Since April 2003, a total of 54 patients have enrolled in the open-label study and, as of March 1, 2005, 44 patients continue to participate in the study and receive ambrisentan therapy.
To date, the results of our Phase 2 trials have demonstrated:
a statistically significant and clinically meaningful increase in the primary efficacy endpoint (six-minute walk test) in all four ambrisentan dose groups;
an improvement in all secondary endpoints and cardiopulmonary hemodynamics;
ambrisentan appears to be generally safe and well tolerated in patients who have received it;
among the patients taking anticoagulant therapy, there are no apparent interactions with anticoagulants requiring dose adjustments;
a low incidence of potential liver toxicity as assessed by liver function tests;
a survival benefit to patients treated with ambrisentan when compared with predicted survival based on the National Institutes of Health Registry formula; and
patients with less severe symptoms (Class II disease) appear to achieve a comparable benefit in exercise capacity as do patients with more severe symptoms (Class III disease). Clinical trial results of other compounds tested for PAH indicate that certain compounds are comparatively less effective in patients with early stages of the disease, referred to as a "ceiling effect."
Abnormal elevations of liver function test (LFT) results, which are indicative of potential liver toxicity, have previously been reported as complications in trials of other endothelin receptor antagonists. LFT abnormalities were defined in our study as a confirmed serum aminotransferase level greater than three times the upper limit of the normal range. During the 12-week blinded treatment period of this trial, one patient was taken off ambrisentan due to an abnormally high LFT result (eight times the upper limit of the normal range). After halting treatment, the patient's serum aminotransferase level returned to a normal level without apparent adverse effects on the patient's health. During the second 12-week open-label extension period, another patient had their dose of ambrisentan reduced due to a confirmed abnormally high LFT result (three times the upper limit of the normal range). Two additional patients had LFT results that fluctuated above the normal range during the open-label extension period, and on one occasion each had an initial LFT result that was marginally above the threshold of three times the upper limit of the normal range, but upon repeat testing, the results were below the threshold. Detailed results of this trial were presented by the principal investigator, Dr. Lewis Rubin, at the annual meeting of the American Thoracic Society on May 23, 2004.
Overview of Current Phase 3 Trials
In January 2004, Myogen announced the initiation of two pivotal Phase 3 clinical trials, ARIES-1 and ARIES-2, evaluating the safety and efficacy of ambrisentan in patients with PAH. The ARIES trials are randomized, double-blind, placebo-controlled trials of identical design except for the doses of ambrisentan studied and the geographic locations of the investigative sites. Both trials were designed to enroll 186 patients (62 patients per dose group). ARIES-1 will evaluate once-daily doses of 5 mg and 10 mg of ambrisentan. ARIES-2 evaluated once-daily doses of 2.5 mg and 5 mg of ambrisentan. The primary efficacy endpoint is exercise capacity, measured as the mean change from baseline at 12 weeks in the 6MWD compared to placebo. Secondary endpoints include time to clinical worsening, World Health Organization (WHO) functional class, SF-36™ Health Survey, and Borg dyspnea index. ARIES-2 enrolled 192 patients primarily from Europe, while ARIES-1 enrolled 202 patients primarily from the United States. The Company expects to report top line results for ARIES-1 in the second quarter of 2006. In addition, more than 300 patients continue ambrisentan treatment in long-term trials with maximum exposure of more than three years.
Enrollment in ARIES-1 was completed in November 2005 and we expect to report top line results in the second quarter of 2005. Enrollment in ARIES-2 was completed in August 2005 and top line results were reported December 12, 2005.
ARIES-2 Results
The trial met the primary efficacy endpoint of improved exercise capacity, the key secondary endpoint of time to clinical worsening and several other secondary efficacy endpoints.
The primary efficacy endpoint of the ARIES-2 trial was the placebo-corrected mean change in six-minute walk distance (6MWD) at week 12 compared to baseline. Results of the trial demonstrated that with once-daily dosing, 5 mg of ambrisentan improved the placebo-corrected mean 6MWD by 59.4 meters (p=0.0002) and 2.5 mg of ambrisentan improved the placebo-corrected mean 6MWD by 32.3 meters (p=0.0219). For the placebo group, the mean 6MWD at week 12 decreased from baseline by 10.1 meters. Improvements in time to clinical worsening compared to placebo were observed for both the 5 mg dose group (p=0.0076) and the 2.5 mg dose group (p=0.0048).
The trial safety results demonstrated ambrisentan was generally well tolerated. The most frequent adverse event was headache, which occurred in 12.7% of patients in the 5 mg dose group and 7.8% in the 2.5 mg dose group, compared to 6.2% in the placebo group. No patients treated with ambrisentan developed serum aminotransferase concentrations greater than three-times the upper limit of the normal range, compared to one patient in the placebo group. Ambrisentan had no apparent effect on the activity or dosage of warfarin-type anticoagulants commonly prescribed for patients with PAH.
In March 2004, we initiated a long-term study of patients who have participated in our pivotal Phase 3 clinical trials of ambrisentan. This study will examine the efficacy and safety of three doses (2.5, 5, or 10 mg) of ambrisentan for a period of 24 weeks followed by a dose adjustment period. Patients who received placebo in the Phase 3 studies will be randomized to receive one of three doses of ambrisentan.