Tacrolimus as a new approach to pulmonary artery hypertension?

I am just sitting here in Dulles airport on the way back from this year's ATS meeting and wanted to share with you a scientific story that has got me quite excited.

Actually I have just been sitting here for rather a long time but that is another story - I am just mentioning this as an excuse for typos etc that may creep in after 24 hours with no sleep.

Just a quick introduction - pulmonary artery hypertension (PAH) is a subset of pulmonary hypertension. PAH is characterized by increased remodelling of the pulmonary artery which takes blood from the right heart to the lung for reoxygenation. The remodeling process results in increased pulmonary artery pressure, right heart enlargement and eventually failure. The disease is rare but often fatal although life expectancy has increased due to a number of advances (prostacyclins, PDE5 inhibitors and endothelin receptor antagonsists).

The reported incidence of PAH is low; 1-5 new cases each year per million people. No one knows exactly what causes PAH - in fact it is an umbrella term for various disease subtypes. It occurs in some HIV patients; metaphetamine users; people with scleroderma; those infected with schistosomiasis (a water bourne parasite). In some patients it is heritable- familial PAH accounts for between 6%-10% and is associated with a defect in a protein called BMPII.

Now onto the exciting part - Stanford researchers have taken a large panel of approved medicines from a broad range of conditions and ran them through an assay of BMPII activity. One molecule lit the assay up - tacrolimus - also known as Prograf or FK506.

Tacrolimus is used in most transplant recipients as an immunosupressant; it prevents the activation of calcineurin and consequent expression of cytokines and their high‐affinity receptors.

In addition to re-expressing BMPII activty, the Stanford group demonstrated that tacrolimus can upregulate the BMPII pathway in cells taken from PAH patients and also correct haematological defect in BMPII KO mice or in a new PAH model induced by SUGEN and hypoxia.

Together these pieces of evidence offer convinging evidence that tacrolimus may just offer hope to some PAH patients - the next step is to test this concept. Tacrolimus has been approved and can therefore be used in patients.

"Viagra to be used for children" - A gripe from LeadDiscovery

I was just going through a batch of press releases and came across one entitled "Viagra to be used for children" - I am not sure whether to congratulate the authors for headline grabing or go after them with a long stick for incompetent reporting.

The story underlying the headline is quite interesting and also a bit of a master stroke froim Pfizer and so I just wanted to take a few moment to explain.

Pretty much everyone knows what Viagra is by now...a bit of a revolution in its time for the treatment of male erectile dysfunction. Viagra has also been highly profitable for Pfizer. In the Q1 2011 figures released last week Pfizer announced that Viagra generated $470 million worldwideand so it remains a blockbluster and Pfizer's 6th highest earner.

In 2005 the EMA and the FDA approved a product known as Revatio. This drug contains the same molecule as Viagra, sildenafil but is used for the treatment of pulmonary hypertension. This is a serious condition that affects the pulmonary valculature of all age groups. Revatio revenue is respectable, $123 million last quarter, but a fraction of that generated by Viagra.

However, the problem for Pfizer is that the patent on sildenafil is soon due to expire. One common approach to increasing revenue of a drug is to get a 6 month paediatric extension. This is obviously not possible for Viagra however pulmonary hypertension does affect children and gaining approval for Revatio in this indication extend the life of both brands. An extra 6 months of sales represents approximatley $200 million in EU sales, and it is the EMA that has recently extended the exclusivity of sildenafil. This figure will increased dramatically if the FDA follows suit although this is not certain at the moment. The reason for this is complicated and I won't go into now.

There is still something irritating about the headlines coming through the wire - Viagra for children? Facgtually incorrect if you want to be picky...the headline should read Revatio for children but who has heard of Revatio? I guess that it is the point.

If anyone is interested in reading more about pulmonary hypertension drug development we recommend:

Pulmonary Arterial Hypertension clinical community builds order from chaos