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Company News: Probiodrug’s Hypothesis on Alzheimer’s Disease Onset Featured in German Radio

During the upcoming World Alzheimer Day, the German MDR radio will feature the efforts by German biotechnology company Probiodrug to develop novel strategies for the treatment of Alzheimer’s Disease (AD). MDR’s FIGARO am Vormittag morning magazine will introduce the company’s hypothesis on the onset of Alzheimer’s Disease (AD) and highlight the latest research results published by Probiodrug and co-workers from German and US research institutions in the recent  Journal of Neuroscience.

It is well known that the presence of so-called beta-amyloid (A beta) plaques in the brain is not necessarily correlated with the occurrence of AD. Probiodrug discovered that in AD patients, the core of the plaques is made form a certain variant of the A beta peptide which is more neurotoxic, less soluble and able to rapidly aggregate with modified and unmodified A beta. Further investigations revealed that this toxic variant is generated by an enzyme called QC (glutaminyl cyclase). QC is responsible for activating certain hormones and enzymes in the brain by modifying a certain chemical group in these molecules. If it starts acting on A beta, it produces the toxic variant. Probiodrug also has demonstrated in various experiments that it is possible to prevent the formation or spread of toxic A beta plaques by switching off the QC enzyme. The company therefore is developing drugs to inhibit the enzyme as a potential treatment strategy to either prevent the onset of AD or slow down the progression of the disease.

Food for Thought: IQWiG Says Benefit Of Ezetimibe Not Proven

Various studies have demonstrated that lowering cholesterol levels with statins is preventing heart attacks and other cardiovascular complications. However, some patients do not tolerate statins or do not achieve recommended cholesterol levels with statins alone. These patients often are prescribed ezetimibe (sold as Ezetrol by MSD Sharp & Dohme in Germany), an oral cholesterol-absorption inhibitor, either alone or in combination with statins. A fixed combination of ezetimibe with statin simvastatin is sold as Inegy.

Last year, Germany’s Federal Joint Committee (G-BA) which is deciding about drug reimbursements for the country’s statutory healthcare system, commissioned Germany’s cost-benefit watchdog IQWiG to assess the benefit of ezetimibe either alone or as combination therapy.

IQWiG published its report earlier this month. While it not disputes that ezetimibe is lowering cholesterol levels, the institute states in its report that it has been unable to identify any review or study demonstrating that the prescription of ezetimibe alone or in combination does provide patient-related benefits in terms of reducing “all-cause” or “vascular” mortality.

However, new data and findings supporting the benefit of ezetimibe will be available soon.  Pulse Magazine, a leading medical weekly in the UK, reported Sept. 2 that researchers looked into the effectiveness of ezetimibe in combination with statins on all-cause mortality over a period of 4.3 years. They concluded that the combination treatment – if used after a myocardial infarction – resulted in a 55% decrease in all-cause mortality compared to patients taking simvastatin alone. The trial was a retrospective study on a cohort of nearly 15,000 patients from the UK’s General Practice Research Database. The researchers already had announced a presentation of the results at the European Society of Cardiology Congress in Paris end of August, but cancelled the presentation to perform a more complex analysis of the data.

Company News: Nanobiotix Starts Clinical Trial with Lead Product NBTXR3

– A Completely New Cancer Treatment to Be Tested in Patients with Soft Tissue Sarcoma –

Nanobiotix, a company developing novel cancer nanotherapeutics, announced today that its lead compound NBTXR3 has received the formal authorization from the French Medicine Agency, AFSSAPS[1], to start the first clinical trial[2].

27 patients diagnosed with soft tissue sarcoma will be enrolled in the Phase I study and will receive NBTXR3 as an intra-tumoral injection with radiotherapy prior to surgery (first-line treatment) (www.clinicaltrial.gov). The primary endpoints of the clinical trial are the feasibility of NBTXR3 administration and safety. Preliminary data are expected by the end of 2012.

The trial is a prospective, open-label, dose-escalation, single arm, non-randomized trial. NBTXR3 will be administered to the patients prior to surgery by a single intra-tumoral injection followed by standard radiotherapy procedure. After completion of the regular treatment procedure, the patients will undergo surgery to resect the soft tissue sarcoma. Along with the safety and feasibility endpoints, the primary tumor tissue will then be available for the evaluation of the pathological response rate.

Further clinical trials are in preparation in Europe and in the US. NBTXR3 has been classified in the EU as class III medical device. In the US, it has been classified as a drug by the FDA.

NBTXR3, the most advanced compound of Nanobiotix´ NanoXray pipeline, is intended to enhance the local destruction of the tumor mass during radiotherapy. NBTXR3 is a nanoparticle consisting of hafnium oxide crystals. Once injected into the tumor, NBTXR3 accumulates in the cancer cells. Due to the physical properties of hafnium oxide, the particles emit huge amounts of electrons upon radiation. This leads to the formation of radicals within the tumor cell, which in turn damage the cancer cells and cause their targeted destruction. NBTXR3 particles are inert and emit electrons only during their exposure to radiotherapy. As a result, the destructive power of standard radiation therapy could be locally and selectively enhanced within the tumor cells.

Local treatment of malignant tumors is a cornerstone of cancer therapy. The standard treatments are surgery and radiotherapy, either as a stand-alone treatment or in combination. Radiotherapy has been widely used across most oncology indications for decades. About 50 to 60% of all cancer patients undergo radiotherapy treatment as part of existing treatment guidelines. All NanoXray products are compatible with these guidelines and do not require changes of surgery and radiotherapy procedures. Moreover, NanoXray products can be used with any existing standard radiation equipment available in almost every hospital world-wide.

[1] Agence Française de Sécurité Sanitaire des Produits de Santé

[2] Clinical trial, registration number RCB 2011-A00342-39

Company News: Neurodegeneration in Alzheimer’s Disease: The crucial role of QC

Probiodrug provides further insights into the onset of AD in The Journal of Neuroscience

Probiodrug AG (Probiodrug), a biotech company developing novel products for the treatment of neurodegenerative and inflammatory disorders, today announced the publication of data providing key insights into the onset and development of Alzheimer’s disease (AD) in the Journal of Neuroscience (http://redir.ec/jneurosci).

AD is characterized by deposition of amyloid-β (Aβ) plaques in the brain. However, quantitative relationship between plaque deposition and severity of cognitive decline in the affected individuals is still elusive. Often, elderly people carry a large amyloid burden without any signs of cognitive impairments, and many animal models of AD also develop the characteristic hallmarks, such as plaques, but do not demonstrate the cognitive defects and loss of neurons typical of the human disease.

Several years ago, Probiodrug developed the hypothesis that the missing link between Aβ load and prevalence of AD is a certain modification of Aβ, in which the Aβ molecule carries a pyroglutamate residue (pGlu) at its N-terminus. This pGlu-Aβ is neurotoxic and develops a strong tendency to aggregate and to seed aggregation of further pGlu-Aβ as well as unmodified Aβ. The modification of glutamic acid to a pGlu-residue is catalyzed by the so-called QC enzyme (glutaminyl cyclase).

In this week’s The Journal of Neuroscience* Probiodrug researchers (and their collaborators from Friedrich Alexander University, Erlangen, the German Center of Neurodegenerative Diseases, Magdeburg, the Leibniz Institute for Neurobiology, Magdeburg, the Paul Flechsig Institute for Brain Research, Leipzig, and the University of Tennessee, Knoxville/ USA) now describe the generation and characterization of a novel animal model that solely expresses N-truncated human Aβ, which in turn is modified by QC to pGlu-Aβ. As a result, these animals which express the toxic species 1000fold less than other models do with Aβ not only have the typical pathological changes, but also neuronal loss and cognitive impairments.

”We now have animal models that represent the full spectrum of pathological and behavioral changes in AD without overexpressing the Aβ peptides. In addition, we could once again clearly demonstrate that the activity of QC enzymes is starting the chain of events that ultimately leads to the debilitating disease, which already affects millions of people world-wide. The results in this study also demonstrate that lowering the QC-dependent formation of pGlu-Aβ reduces the amount of neurotoxic aggregations, and further strengthens the hypothesis that inhibition of QC is a promising new treatment strategy for AD” commented Hans Ulrich Demuth, CSO of Probiodrug.

*doi:10.1523/JNEUROSCI.2172-11.2011

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