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.

Erythromycin as an antiinflammatory/treatment of diabetic nephropathy

Today's edition of DailyUpdates from LeadDiscovery highlights what we felt to be a particularly interest study demonstrating the efficacy of erythromycin in diabetic rats. In particular, this study shows that erythromycin is able to ameliorate renal injury through the modulation of inflammation. The title of the study is "Erythromycin ameliorates renal injury via anti-inflammatory effects in experimental diabetic rats" and it was published in Diabetologia. 2005 Oct 18; [Epub ahead of print]. The abstract is below.

One of the reasons why we found this report so interesting was that diabetic nephropathy remains a serious clinical concern. In fact in their in depth evaluation of this field Diabetic Nephropathy: Prevalence, Progression, Prevention and Potential conclude that diabetic nephropathy is the most common cause of end-stage renal disease in the US and Europe. Despite the efforts to address the increasing incidence of both type 1 and type 2 diabetes, the diabetic population is set to increase by 72% between 2003 and 2025 and therefore diabetic nephropathy is likely to remain a major cause of death unless improved treatments are identified.

The Diabetologia study featured in DailyUpdates is therefore of interest since it may hold the key to improved therapeutics. The data suggest that companies may wish to evaluate the therapeutic potential of erythromycin-like molecules, outside the field of infectious diseases, in greater detail. Presumably this is relevant to inflammatory diseases in general and not just the inflammatory component of diabetic nephropathy.

Having conducted a very preliminary search of PubMed we were unable to find much in the way of information on the anti-inflammatory properties of erythromycin. We aim to expand on this over the next few hours but if any visitors to this forum would like to provide information on this topic it will be gratefully received.

Likewise, since erythromycin has been known for a long time libraries of erythromycin-like molecules are sure to exist somewhere - does anyone know of such a library and has this been screened for anti-inflammatory activity? We will also be chasing up this information but feel free to post a comment if you know of such libraries.

Publisher's Abstract

AIMS/HYPOTHESIS: Recent studies have shown that the inflammatory process is involved in the pathogenesis of diabetic nephropathy. Fourteen-membered ring macrolides, including erythromycin, have anti-inflammatory, as well as antibacterial effects. The aim of this study was to investigate the renoprotective effects of erythromycin in streptozotocin (STZ)-induced diabetic rats. METHODS: STZ-induced diabetic rats were treated orally with erythromycin (5 mg/kg body weight) or vehicle every day for 8 weeks. To evaluate the effect of erythromycin treatment, we measured urinary albumin excretion, and examined the following in the kidney: histological changes, the expression of intercellular adhesion molecule-1 (ICAM-1), macrophage infiltration, and nuclear factor-kappa B (NF-kappaB) activity. RESULTS: Erythromycin significantly reduced urinary albumin excretion without affecting blood glucose levels and blood pressure. Erythromycin also attenuated glomerular hypertrophy, mesangial expansion, macrophage infiltration and ICAM-1 expression in renal tissues. The expression of the gene encoding TGFB1 (also known as TGF-beta1), type IV collagen protein production and NF-kappaB activity in renal tissues were increased in diabetic rats and reduced by erythromycin treatment. CONCLUSIONS/INTERPRETATION: Erythromycin prevented renal injuries without changes of blood glucose levels and blood pressure in experimental diabetic rats. These results suggest that the renoprotective effects of erythromycin are based on its anti-inflammatory effect via suppression of NF-kappaB activation. Modulation of microinflammation with erythromycin may provide a new approach for diabetic nephropathy.

Venlafaxine XR as an effective treatment of depression in patients that fail to respond or are intolerant to other antidepressants

In the August, 2005 edition of the journal Depression & Anxiety, Baldemero et al published a report "Venlafaxine extended release versus conventional antidepressants in the remission of depressive disorders after previous antidepressant failure" [abstract]. This was selected for inclusion on LeadDiscovery's November 9th edition of DailyUpdates-Psychiatric, Sleep & Addictive Disorders as our editors considered this study important both with regard to the treatment of depression and the dynamics of the antidepressant market

Major depressive disorder affects an estimated 340 million people worldwide making it the fourth greatest public health problem. In addition to the personal costs of depression, the disorder also results in more than $40 billion in annual costs in the US alone, due to premature death, lost productivity and absenteeism.

The serotonergic class dominates the market, accounting for 58% of market share in 2002. This class includes the serotonin reuptake inhibitors (SSRIs) however only 40–50% of patients achieve response or remission when treated with SSRIs. The serotonergic class also includes dual reuptake inhibitors, often referred to as SNRI which simultaneously block serotonin and norepinephrine uptake. The dual reuptake inhibitors are led by Wyeth’s Effexor which, according to its manufacturer helps significantly more patients achieve remission and resolution of both emotional and physical symptoms than SSRIs. Lilly’s launch of the dual reuptake inhibitor Cymbalta in 2004 represents the first major challenge to Effexor.

An estimated 25-30% of patients fail to respond to antidepressant treatment while a further 10–20% fail to tolerate it, and patients that fall into either of these categories are often switched to a different antidepressant. At present the preferred choice of second line antidepressant is unclear however given the high rate of switching the identification of such a second line treatment would carry a significant market advantage to that therapeutic.

In the August, 2005 edition of the journal Depression & Anxiety, Baldemero and colleagues report the findings of a randomized, open-label, multicenter study comparing effectiveness of venlafaxine XR with that of conventional antidepressants in patients who were referred to an outpatient psychiatric specialty care setting for treatment after failure to tolerate or respond to at least 4 weeks of treatment with a conventional antidepressant in a primary care setting.

Patients who had failed to tolerate or respond to conventional antidepressant treatment in a primary care setting were randomly assigned to treatment with an alternate conventional antidepressants or venlafaxine XR. The antidepressants prescribed most frequently in the conventional antidepressants group were paroxetine, citalopram, sertraline, fluoxetine and mirtazapine. After 24 weeks of treatment, the venlafaxine XR group demonstrated a significantly higher remission rate (59.3%) than did the conventional antidepressants group (51.5%), paralleling this improvement venlafaxine XR produced a greater response. Furthermore both patients and clinicians both reported a very much improved level of depression more frequently when treated with venlafaxine XR as compared to other antidepressants. When compared to conventional antidepressants individually, venlafaxine XR was superior to each of these compounds. On the basis of the current study venlafaxine XR appears to be a antidepressant of choice in patients unresponsive to or intolerant of conventional SSRIs. This will need to be born out by double-blind trials however if this is indeed the case the sales of venlafaxine XR stand to be boosted still further.

The antidepressant market is set to undergo a period of rapid change as seven out of the eight leading brands suffer US patent expiries by 2008 (see Antidepressants - Sliding SSRI Revenues Inevitable). With only a handful of new products anticipated to replace these blockbuster products, Datamonitor conclude in this report that the market will decrease by 21.5% to $13.5 billion by 2011, as physicians are encouraged to utilize cheaper generics. Datamonitor also conclude that brand players should be looking towards maximizing revenues through product differentiation and innovative lifecycle strategies. The present study by Baldemero et al goes part of the way to this goal differentiating further, venlafaxine XR from conventional SSRIs with respect to its second-line potential. This coupled with improved efficacy in a first-line setting should maximize its revenue generating potential.