Progress in the treatment of peripheral arterial disease (PAD)
SummaryIn contrast to coronary and cerebral artery disease, peripheral arterial disease (PAD) remains an under-appreciated condition that despite being serious and extremely prevalent is rarely diagnosed and even less frequently treated. This situation is now changing as physician awareness grows in parallel with increased use of existing therapeutics and the development of improved cardiovascular agents, gene therapies and devices
Special Feature - Progress in the treatment of peripheral arterial disease (PAD) (Source LeadDiscovery - January, 2005)
In contrast to coronary and cerebral artery disease, peripheral arterial disease (PAD) remains an under-appreciated condition that despite being serious and extremely prevalent is rarely diagnosed and even less frequently treated. This situation is now changing as physician awareness grows in parallel with increased use of existing therapeutics and the development of improved cardiovascular agents, gene therapies and devices.
PAD, an underdiagnosed health problem: The prevalence of PAD has usually been cited as 8-12 million people in the US however data from the SAGE group presented in this report suggest that total numbers could be as high as 20 million. Even when a more conservative figure of 14 million is taken for the prevalence of PAD this far outweighs all other serious diseases other than that of diabetes. Between 2004 and 2020 the prevalence of PAD is predicted to increase by 43%. This growth will mainly result from the increase in physician awareness of the disease, leading to more screening and thus more diagnoses of PAD.
The underappreciated & serious problem of asymptomatic PAD: Early symptoms of PAD include transient pain in the legs upon walking (intermittent claudication) caused by ischemia. Up to 25% of these ischemic patients will progress to develop critical limb ischemia (CLI) frequently requiring amputation and associated with heightened mortality rates. The majority of PAD patients do not however develop critical limb ischemia and this group has often been described as asymptomatic. This is not true since these patients experience a loss of mobility and furthermore an increased mortality rate. Altogether 30% of patients with PAD will die within 5 years rising to 50% after 10 years representing an increased mortality rate exceeding most other conditions including coronary artery disease and breast cancer.
Lack of physician awareness contributes strongly to the lack of appreciation of PAD: In total it is estimated that less than 20% of PAD patients are diagnosed and unsurprisingly up to 80% of primary care physicians have requested further education into PAD. Leading groups including the Society of Interventional Radiology and the National Heart, Lung & Blood Institute have accelerated programs to improve both physician and public awareness of PAD in recent years.
Existing therapeutic agents could offer treatment options for PAD: In a detailed analysis of patients needs, The SAGE group estimates that 25% of patients with PAD require claudication agents; 50% would benefit from anti-hypertensives; 90-100% should receive lipid lowering agents and all patients are suitable for antiplatelet therapy. Incredibly however few cardiovascular drugs are indicated for the treatment of PAD. For example no statins (the gold standard in lipid lowering agents) are indicated for PAD. Clinical studies that result in PAD being added as an indication for statins or which prompt off-label use of this class could double the $13 billion market for lipid lowering agents. Likewise the market value of anti-hypertensives could be doubled; claudication drug revenue could increase by as much as 6-fold; and perhaps most dramatic is the forecast 10-fold increase in sales of the anti-platelet agent, Plavix. At present Plavix is indicated for the reduction of atherosclerotic events (myocardial infarction, stroke, and vascular death) in patients with atherosclerosis documented by recent stroke, recent myocardial infarction, or established PAD, but not for the treatment of PAD itself. Companies may either decide to conduct formal trials of existing cardiovascular agents in PAD patients or alternatively efforts may be focused on pipeline therapeutics.
Novel therapeutics are being developed for the treatment of PAD: There are seven anti-platelets in development for the treatment of intermittent claudication, four of which are being developed by Japanese companies. Nissan Chemical Industries is developing NM 702 in Japan and the US in collaboration with Taisho Pharmaceuticals. A Phase IIa clinical trial of the drug, conducted in the US in PAD patients with intermittent claudication, yielded results showing promising efficacy. Sales of NM 702 are forecast to reach $67m in 2012.
NCX 4016 (NO-aspirin) is a nitric oxide-releasing non-steroidal anti-inflammatory drug. As a thromboxane inhibitor, NCX 4016 works via a different mechanism of action than clopidogrel and it is expected that aspirin/clopidogrel combination will be replaced by NCX 4016/clopidogrel combination. Only last week, NicOx announced that it has completed full recruitment in its phase II trial of NCX 4016 for the treatment of PAD. Sales of NCX 4016 are forecast to experience a sharp increase from 2010 onwards, with sales reaching $123m in 2012. Like NM 702, NCX 4016 is being evaluated in patients with intermittent claudication and it is not known whether studies are planned to investigate these agents in the vast majority of patients with so-called asymptomatic disease
Interventionist opportunities for severe disease: When disease is too severe to be treated pharmacologically a variety of interventional therapies are indicated. As well as depending on level of ischemia, the choice of interventional treatments for PAD is dictated by the anatomy of disease. Bypass surgery produces frequent and long-lasting patency and is therefore the gold standard interventional therapy for PAD. Bypass, either with one of a large number of artificial grafts or using an autologous graft is particularly indicated in patients with long and/or diffuse disease or disease associated with aneurisms or atheroemboli. Due to its invasive nature bypass surgery does however carry a relatively high incidence of mortality and morbidity. Restenoses and embolisms are also relatively common albeit treatable risks.
Angioplasty is becoming an increasingly popular strategy for PAD: Less invasive endovascular procedures are becoming more popular. Associated with a considerably reduced morbidity compared to bypass, increased cost-effectiveness, but much more frequent restenosis, angioplasty is the most common endovascular procedure. In addition a wide variety of stents are also used as are, much less frequently, atherectomy devices. Over the past 20 years angioplasty and/or stenting has replaced bypass as the initial treatment of choice for aortoiliac disease, in particular in patients with short stenoses devoid of aneurysms or embolisms. In contrast to aortoiliac disease, the much more frequent femoropopliteal lesions are difficult to treat with angioplasty, and instead new stenting technology offers a useful approach. Uptake of this technology will however depend on the issue of stent fracture being addressed and on the further development of drug eluting stents. Like patients with femoropopliteal disease, patients with tibioperoneal PAD are generally unsuitable for angioplasty. Rather than bypass experts now believe that endovascular interventions, and in particular laser or cutting balloons, are the preferred treatment strategy.
Early intervention is now advised for the treatment of PAD: Endovascular procedures are more successful and have fewer side-effects when conducted early in the course of disease and experts now recommend that intervention should be practiced sooner and more aggressively in order to prevent progression to critical limb ischemia. A shift in practice is already underway with the number of endovascular procedures almost trebling between 1983 and 2000. There is however room for considerably more growth and it is estimated that the total potential market for endovascular procedures currently stands at 5.2 million compared to the 0.6 million procedures actually conducted.
Gene therapy as a novel approach to PAD: The most novel therapy in development is angiogenic gene therapy, which could prevent limb loss in patients with end-stage PAD. However, gene therapy is still controversial as its long-term efficacy and side-effects are unknown. Sanofi-Aventis’s NV1FGF is the most promising agent in development and is expected to reach the market by 2008. Through gene therapy, genes encoding vascular growth factors can be introduced into the lower leg muscles to cause muscle cells to secrete growth factors to induce the development of new collateral blood vessels. Although there is the risk that angiogenic gene therapy could promote tumor growth in at risk individuals no malignant transformations have been observed. A greater problem is the suggestion that although gene therapy may stimulate neoangiogenesis, the newly formed vessels may be functionally abnormal.
Of the three gene therapies predicted to be launched in the coming decade, Sanofi-Aventis’s NV1FGF is the most promising. NV1FGF uses a non-viral vector for the delivery of FGF and is in Phase II of development for PAD in Germany, France, Italy Switzerland, the UK and the US. The agreement between Sanofi-Aventis and Vical allows Sanofi-Aventis to use Vical’s naked DNA technology to deliver the FGF gene. Phase I results are promising and global sales of NV1FGF are forecast to grow from $100m in 2008 to $687m in 2012.
The first steps on the road to improved treatment have been taken: Over recent years awareness of PAD has grown tremendously and the first hurdle has now been passed. As the true numbers of patients becomes more apparent and the morbidity associated with the disease is better defined therapeutic opportunities will unfurl. This is likely through the greater use of existing agents and the development of new ones. Optimizing this process will require formal studies to be conducted in PAD patients and ideally these will not be limited to those with intermittent claudication. In addition the development of improved interventional strategies (including drug eluting stents) and in the more long-term, gene therapies, will offer further hope to patients.
For further information see
- Pipeline therapeutics for peripheral arterial disease (PAD)
- The Cardiovascular Report
- Reducing inflammation as an emerging target for cardiovascular disease
- Peripheral arterial disease (PAD): A Significant Opportunity for Interventional Therapies
- Peripheral arterial disease (PAD): prevalence, current treatments & new technologies
- Antihypertensives - Together We Stand, Divided We Fail