Cardiovascular potential, cardiovascular risks of targeting PDE4

Today's edition of DailyUpdates from LeadDiscovery highlights a study by Lenhart and colleagues from Columbia university investigating the role of PDE4 in heart failure. The data presented suggest that PDE4D3 levels were reduced in failing human hearts and that this could contribute to the progressive loss of cardiac function. We felt that this was interesting for two reasons. Firstly with respect to the development of new therapeutics for heart failure and second regarding possible adverse effects of PDE4 inhibitors being developed for other indications. The title of the study is " Phosphodiesterase 4D Deficiency in the Ryanodine-Receptor Complex Promotes Heart Failure and Arrhythmias” and was published in last months edition of the journal Cell (2005 Oct 7;123(1):25-35). The abstract is below.

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During the past two decades, heart failure has emerged as a major chronic disease among the elderly population in the major pharmaceutical markets (see LeadDiscovery’s feature Heart Failure - Pumping Up Therapy Will Prevent Failure). The leading cause of hospitalization among patients over the age of 65 in Western markets, heart failure represents a major burden for healthcare systems but is a highly attractive development market for pharmaceutical and medical device companies. The diagnosis and treatment of chronic heart failure is sub-optimal with physicians failing to follow established guidelines. This suggests the need for continued physician education and a greater communication between the various physician types who manage heart failure patients. Even when heart failure is recognized suboptimal treatments contribute to the growth of heart failure as a major societal burden.

PDE4 exists as 4 isoforms, PDE4A-D, and each of these isoforms exists as multiple splice variants. The highlighted study is of interest showing that reduced PDE4D3 levels are observed in failing human hearts and this could contribute to the progressive loss of cardiac function. We ask whether gene therapy to reintroduce this enzyme could represent a novel approach to heart failure? Over the past year DailyUpdates has featured a number of studies report successful gene therapy as an approach to cardiovascular patients. In particular VEGF expression has been induced in cardiovascular tissue to stimulate angiogenesis and neovascularization. The authors of the Cell study suggest that reduced PDE4 functionality leads to PKA-hyperphosphorylation of "leaky" RyR2 channels that promote cardiac dysfunction and arrhythmias. The development of PKA inhibitors as a treatment of heart failure may therefore be another therapeutic approach and we would be interested to here the views of our readers on this subject.

Viewing the Cell data from the opposite direction we ask whether PDE4 inhibitors currently in development could be at risk of worsening heart failure. A number of PDE4 inhibitors are in development, the most advanced of which is Altana’s Daxas. This therapeutics class is being developed for airway inflammation associated with chronic obstructive pulmonary disease (COPD) and asthma (for details on this field see Pipeline Insight: Asthma, COPD and Allergic Rhinitis Therapeutics).

COPD, comprising chronic obstructive bronchitis and emphysema, represent a major global healthcare problem. World-wide, 600 million people suffer from these diseases with some three million dying as a result each year. COPD is caused by chronic respiratory inflammation, proteolytic breakdown of airway tissue and consequent loss of elastic recoil in the lungs. This serious healthcare problem is paralleled by global sales of around US$2.8 billion which will increase in value significantly over the next decade. One of the primary drivers for this field will be the development of novel disease modifying therapeutics since options for the treatment of COPD are limited. In fact Boehringer Ingelheim’s recently launched Spiriva was the first specific drug for COPD.

Considerable hope has been attached to the PDE4 inhibitor Daxas (Roflumilast) for the treatment of asthma and chronic obstructive pulmonary disease and Altana filed for approval in European countries in February 2004. Submission was based on promising clinical data. The RATIO trial demonstrated, according to Altana, that Daxas produces sustained improvement of lung function and a good safety profile over a one year period. The lung function (FEV1), a primary endpoint of the study, improved significantly with a roflumilast therapy over placebo. PEGASUS1, a second trial conducted in the United States also demonstrated improved lung function. In November 2005 however Altana withdrew its submission after it had reached a deal with the European regulators. This deal will apparently involve Altana obtaining further clinical data on Daxas.

Since Roflumilast is relatively non-selective across the various PDE4 enzymes, one of the risks is, that based on the data highlighted today, roflumilast could worsen heart failure if the treated patient has this disease as an underlying condition. Unfortunately heart failure and COPD commonly co-exist. Further clinical development of roflumilast as well as the PDE4 inhibitor class will hopefully address this potential problem.

Publisher's Abstract (see Cell (2005 Oct 7;123(1):25-35))

Phosphodiesterases (PDEs) regulate the local concentration of 3',5' cyclic adenosine monophosphate (cAMP) within cells. cAMP activates the cAMP-dependent protein kinase (PKA). In patients, PDE inhibitors have been linked to heart failure and cardiac arrhythmias, although the mechanisms are not understood. We show that PDE4D gene inactivation in mice results in a progressive cardiomyopathy, accelerated heart failure after myocardial infarction, and cardiac arrhythmias. The phosphodiesterase 4D3 (PDE4D3) was found in the cardiac ryanodine receptor (RyR2)/calcium-release-channel complex (required for excitation-contraction [EC] coupling in heart muscle). PDE4D3 levels in the RyR2 complex were reduced in failing human hearts, contributing to PKA-hyperphosphorylated, "leaky" RyR2 channels that promote cardiac dysfunction and arrhythmias. Cardiac arrhythmias and dysfunction associated with PDE4 inhibition or deficiency were suppressed in mice harboring RyR2 that cannot be PKA phosphorylated. These data suggest that reduced PDE4D activity causes defective RyR2-channel function associated with heart failure and arrhythmias.