Thursday, May 19, 2011

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.

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Tuesday, May 10, 2011

"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

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Wednesday, May 04, 2011

As the HCV field continues to move forward all looks rosy for telaprevir but we are not so sure about boceprevir

Lots of headlines are coming through the newswires now about last week's unanimous decisions by the FDA's advisory panel to approve two new HCV candidates, telaprevir (Vertex/Janssen) and boceprevir (Merck).

On the surface things look pretty good for both compounds, however look below the surface a bit and you will see that telaprevir has come out of last week better off.

Blog continued below


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Both protease inhibitors are clearly able to increase cure rate in HCV patients dramatically. Adverse effects don't even look too bad now and physicians should be able to manage them. Two issues are however worth mentioning about the adverse events.

For telaprevir, the main problem has been known for quite a while now - rash. Vertex/Jannsen designed a rash management program for the Phase 3 trials and it has succeeded, at least in part. The incidence of discontinuation of treatment due to rash has progressively fallen - this is due in part to the use of topical agents to reduce rash but also an understanding that discontinuing telaprevir while continuing with background PEG-INF and ribavirin (HCV standard of care) allows rash to resolve while continuing to eradicate the virus.

The current issue about rash is translating the Phase 3 program to a program that is easy to use in the real world. The real challenge is perhaps to enable non-specialist physicians to be able to distinguish minor rash from severe rash and severe rash from a group of very serious skin conditions known as SCAR.

The safety problems faced by boceprevir are however more serious. The major problem is the anaemia that frequently develops in patients. Anaemia is already a problem in HCV treatment due to ribavirin affects - boceprevir makes the problem worse. The problem faced by the regulators is that it is difficult to asses just how bad the problem is; moreover it is difficult to determine the effects of anaemia in patients treated with boceprevir.

Assessing the degree of anaemia is difficult for two reasons. Firstly baseline haemoglobin levels varied in the Phase 3 trials - secondly physicians were able to use erythropoitin (EPO) in the boceprevir studies (this was not allowed in the telaprevir studies). On a related matter, use of EPO creates its own problems - firstly it is associated with adverse events of its own; secondly it has not been approved for use in HCV; and thirdly it is expensive. Alternatives to EPO are ribavirin dose reduction and this is the approach preferred by Merck. However, there is no comparison of ribavirin dose reduction and EPO use. The study looking at this, PROVIDE, is coming and it may be that the FDA will wait until they see the data before approving boceprevir.

PROVIDE is important for a second reason. Pivotal telaprevir studies allowed the enrollment prior null responders; this was not the case for boceprevir studies. Merck has however now tried to get an indication for null responders. As one of the advisory committee members put it, Merck has "tortured the data to death". In effect it has said patients with a <1 log drop in the lead-in phase used in its pivotal studies are the same as those with a<2 log drop at week 12 - the definition of null responders. Patients with a <1 log drop in the lead in phase are able to show pretty good SVR rates (about 40%) if boceprevir is added to the treatment regimen. The advisory panel did not buy this entirely last week and instead Merck may have to rely on PROVIDE. The study included patients who were characterized as "real null patients". Boceprevir was able to eliminate virus in an appreciable number of these patients at the end of treatment in PROVIDE. However we are still at least 12 weeks off of SVR data from the study and again the FDA may wait until it sees this data prior to approval.

So that is the second reason why Merck may have problems. The third reason is that Merck was highly criticized last week for a lack of drug interaction studies. We don't know yet how boceprevir interacts with antidepressant or methadone. It is quite possible that if used in the real world, patients on antidepressants (of which there are many with HCV - PEG-INF actually produces depression as an adverse event) may be at increased risk of suicide if boceprevir is co-administered. In fact the FDA concluded in its review that rates of depression were higher in boceprevir treated arms. Perhaps drug interaction is the reason why. Equally it is possible that ex-drug users will relapse if boceprevir alters the behavior of methadone. Just as serious drug interactions could diminish the concentration of boceprevir increasing the risk of resistance.

A final reason why Merck may have problems is that it the boceprevir treatment regimens are complex. Depending on the patient's characteristics there are about 5 different treatment schedules. As another panel member put it last week - you have to be a Talmudic scholar to use boceprevir.

So all in all, although both agents received unanimous recommendations for approval last week, we would not be surprised if final approval of boceprevir by the FDA is delayed giving telaprevir first to market advantage. Even if both are approved we believe that, at least until Merck releases more data to allay those concerns described above, physicians will prefer telaprevir as the more simple option for treating HCV.

LeadDiscovery has no relationships with any of the companies discussed in this blog

Further reading:

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