Actelion Preparing to Counter Gilead in PAH

Gilead Sciences' $GILD rival Actelion $ATLN gave full year results today and they were positively received.  As ever with biotech and pharmaceutical companies, investors will always want to focus on the pipeline in order to decide whether the stock is worth buying. Going forward the key event driver for Actelion will be Macitentan. Gilead was featured extensively in an in depth article on earnings view. Before going into more detail, it might be worthwhile to understand the background.


Tracleer vs. Letairis in Pulmonary Arterial Hypertension

Actelion is a rival to Gilead because they compete in Pulmonary Arterial Hypertension (PAH). Gilead's Letairis seems to be gaining market share on Actelion's blockbuster drug Tracleer. Interestingly, in an attempt to broaden their indications, both drugs were put into phase III trials for Idiopathic Pulmonary Fibrosis (IPF) and both failed last year!

The advantage of Letairis is that it is taken on a once a day regimen (as opposed to twice for Tracleer) and has a more flexible dosing regime. In addition, it has demonstrated a superior liver toxicity profile to Tracleer.

According to Trista Morrison in Bioworld, Letairis has demonstrated superior efficacy to Tracleer:

“ the 5mg dose of Letairis... ...increased the distance covered during a six-minute walk by a mean of 31m in one trial and 59m in the other." and "10mg dose... ... increase was 51m. In the Tracleer Phase III, the 125mg dose increased distance by a mean of 35m in one trial and 76 meters in the other. “

As noted in a previous article on Gilead, Letairis has been expanding sales strongly. Although Letairis does have some potential side effects. On the downside, Letairis (ambrisentan) has been linked to an increased risk of peripheral edema (or oedema) and the FDA approved safety labelling revisions according to Yael Waknine:

“Peripheral edema is a known class effect of endothelin receptor antagonists and is also a clinical consequence of (PAH) and worsening PAH. However, clinical study data have revealed an increased incidence of peripheral edema in patients receiving 5 or 10 mg/day of ambrisentan vs. placebo (17% vs. 11%)."

The article goes on to point out that the majority of the cases were mild /moderate in severity, and they occurred with greater frequency and severity in old patients.

So what is PAH and how do these drugs differ?

Pulmonary Arterial Hypertension

One of the problems with pulmonary arterial hypertension is that it is difficult to detect early on. Symptoms include things like chest pain, shortness of breath, palpitations, excessive fatigue and fainting. These symptoms are often mistaken for other conditions, particularly as PAH is not a widely held condition. The cause of PAH is unknown and, ultimately, the condition will cause death. Therefore, treatments are focused on improving survival rates via blocking either ETA receptors or ETA and ETB receptors.

 

Endothelin ETA and ETB Receptors

Endothelin is a powerful vasoconstrictor which has diverse actions that effect homeostatic actions in the body. According to Schneider et al the two receptor subtypes, ETA and ETB

"mediate the actions of endothelin. ETA receptors.. ..promote vasoconstriction, growth, and inflammation, whereas ETB receptors produce vasodilation, inhibit growth and inflammation. Potent and selective receptors... ...have shown promising results in the treatment of.. ..pulmonary arterial hypertension, acute and chronic heart failure, hypertension, renal failure, and atherosclerosis.”

ETA and ETB receptors have opposing actions and it is this contradiction which defines the competition between Actelion’s Tracleer (blocks ETA and ETB receptors) and Gilead’s Letairis (blocks ETA receptors only).


Actelion's Plans for Macitentan in PAH and IPF

Similarly, Actelion's Macitentan blocks ETA and ETB receptors. More light on Macitentan was shed by Iglarz et al:

“optimized for its potency and dual blockade of ETA and ETB receptors since both receptors mediate the deleterious effects of ET-1 in pathology” and “dual antagonism was superior to ETA-selective antagonism in terms of maximal efficacy. This ranking of efficacy between selective and dual antagonism in pathology is inverse in physiology, where in healthy subjects, ETA-selective antagonists induced greater vasodilation than dual"

Actelion has Macitentan in Phase III and it appears that this will be the focus of their efforts in order to retain leadership in PAH after Tracleer’s patent expiry in 2015. In common with Tracleer, It is a dual endothelin receptor antagonist. However, unlike Tracleer, it has shown good efficacy in idiopathic pulmonary fibrosis.

Macitentan Advantages and Timeline

Macitentan is well tolerated and seems to be free of many of the potential liver toxicity issues that are associated with Tracleer and Gilead’s Letairis. According to Martine Clozel,

"Macitentan is expected to protect tissues from the deleterious effect of elevated ET, via a comprehensive blockade of ET receptors in the tissue compartment.”

Unlike Tracleer (but in common with Letairis) it is a taken once a day and has demonstrated greater efficacy than both in pulmonary arterial hypertension. After the intended Phase III and FDA approval Actelion would hope for Macitentan to replace Tracleer and also to open up the IPF market for them.

 

Phase III results for Macitentan in PAH are expected in late 2011 or early 2012, whilst Phase II results for Macitentan in IPF are expected in the second half of 2011. There are exciting days ahead for Actelion!

 

 

 

 

Sources:

Clozel, Martine “Better by Design- Potential of Tissue Targeting”  Abstract from7th International Pulmonary Hypertension Forum, 2008
Iglarz M. et al. “Pharmacology of Macitentan, an orally active tissue targeting dual endothelin receptor antagonist.” J Pharmacol Exp Ther. 2008 Sep 9
Morrison, Trista “Gilead Gets Letairis Approval, Potential Best In Class For PAH”  Bioworld Today, 2007
Schneider, Markus P., Erika I. Boesen and David M. Pollock “Contrasting Actions of Endothelin ETA and ETB Receptors in Cardiovascular Disease” Pharmacology and Toxicology, Volume 47, 2007
Waknine,Yael “FDA Safety Changes: Serevent Diskus, Letairis, Antibiotics”  Medscape News,2008