Monday, January 23, 2006

Busting clots and killing tumors.

In today’s edition of DailyUpdates we feature news on Nuvelo’s candidate for cardiovascular disease, alfimeprase, plus breaking research on thioredoxin inhibitors for the treatment of cancer .

Our headline press release concerns the development of Nuvelo’s candidate treatment for acute peripheral arterial occlusion (also known as acute limb ischemia), alfimeprase. This announcement comes on the same day that we release an in depth report on this field by our partners at The Sage Group (Acute Limb Ischemia Acute Limb Ischemia - A market of multiple therapies and multiple procedures)

Acute limb ischemia is a common yet unmet condition representing the most serious form of peripheral arterial disease (PAD) and is caused by a sudden decrease or worsening of limb perfusion following thrombosis or an embolism (usually in patients with atrial fibrillation). Caused by smoking, diabetes and other risk factors that precipitate peripheral arterial disease, acute limb ischemia is associated with high mortality and amputation rate. Within the first 30 days of ischemia, up to 15% of patients will die while as many as 30% will suffer amputation. These rates rise dramatically over time with mortality reaching over 60% within 5 years, worse than in patients with other cardiovascular diseases or the most common malignancies.

Depressingly, one of the primary treatments of acute limb ischemia is amputation, which represents the first line approach in as many as 70% of patients, a hugely worrying statistic given the cost and reduced quality of life associated with such procedures. More conservative approaches represent a clearly unmet area usually comprising a multi-modal strategy of anticoagulant therapy, surgery (usually embolectomy or bypass), or clot disruption. The benefits of embolectomy (distension of the blocked vessel using a balloon catheter) are frequently limited in acute limb ischemia and instead thrombolytic and interventional approaches to clot removal are more useful.

Although thrombolytic therapy is well practiced in cardiovascular medicine no thrombolytics have yet been approved for the treatment of acute limb ischemia. This is worrying considering the prevalence of disease. Figures from 1997 suggest that 50,000 in the US suffer acute limb ischemia however as discussed in our feature, these numbers are a gross underestimation. Nuvelo seem to be making important headway in this condition with the development of Alfimeprase (currently in phase III studies).

Alfimeprase a recombinant protein able to directly degrades fibrin within thrombi. In clinical studies to date, alfimeprase has been shown to resolve peripheral arterial clots within four hours of initiation of dosing. In addition, its lytic activity is localized to the site of delivery due to its rapid inhibition by endogenous alpha-2 macroglobulin.

Alfimeprase is also in development for the potential treatment of catheter occlusion, clearing occluded catheters in 15 minutes or less; it and may have utility in a wide range of additional thrombotic-related conditions such as stroke, deep venous thrombosis and myocardial infarction. In their report The Sage Group forecast that Alfimeprase will be generating over $300 million in US sales by 2010 for the treatment of acute limb ischemia alone.

Also headlined in DailyUpdates today is a Clin Cancer Res paper that reports an association between thioredoxin and drug resistance in breast cancer patients.

In the course of normal metabolism, oxidizing equivalents or reactive oxygen species (ROS) are generated when oxygen is partially reduced as electrons leak out of the electron transport chain during respiration in mitochondria. Other endogenous enzyme systems also produce ROS and overly high levels of these molecules can produce cytotoxic "oxidative stress". To counteract the effects of oxidative stress, cells have developed defense mechanisms including glutathione, thioredoxin and various enzymes such as superoxide dismutase, catalase, and glutathione peroxidase.

Certain chemotherapeutic agents used in the treatment of cancer increase ROS levels thereby killing tumors, an effect that can be reversed by artificially increasing thioredoxin levels. Elevated levels of thioredoxin have also been observed in several human bladder and prostatic cancer cell lines resistant to chemotherapy. The Clin Cancer Res paper takes these observations forward demonstrating a role of thioredoxin in drug resistance in primary breast cancer samples.

Kim and colleagues demonstrate that docetaxel produced a lower response rate in tumors with high thioredoxin expression compared to those with low thioredoxin expression. Furthermore thioredoxin expression significantly increased after docetaxel therapy. These data suggest that inhibiting thioredoxin may be a useful approach to improving the efficacy of chemotherapy and indeed, in today’s DailyUpdates we report on an announcement by ProlX Pharmaceuticals' who have just enrolled the first patient in a Phase IB clinical trial of their thioredoxin inhibitor, PX-12, in patients with advanced gastrointestinal cancers.

PX-12 has shown encouraging safety and efficacy data in an initial Phase I trial and it is hoped that this will be extended into more advanced studies.


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