- First evaluation of survival times provides results that exceed expectations
- Immunological active principle proven in an exemplary manner
- Data presented at the annual meeting of the American Association for Cancer Research

In a further evaluation of the phase I/II renal cancer study with MGN1601, the biotechnology company MOLOGEN AG has analyzed the survival times of patients enrolled in the study and the first data of the accompanying immunological tests. The result: patients that were able to completely finish the twelve-week therapy scheme scheduled in the study protocol with the study drug MGN1601 (PP group) have an unexpectedly clear survival benefit in comparison with patients that had to terminate their study therapy early (non-PP group).

Thus far, the ten patients in the PP group already survived more than ten months on average. Since only one patient in this group has died by now, this parameter will continue to improve. In the non-PP group, the median survival time is a little over two months; all nine patients had died at the latest after six months. With regard to historical clinical data and statistical models, a median survival time of five to seven months was expected. Hence, this was clearly exceeded in this study.

Furthermore it is very remarkable that for two patients who are currently being treated in the extension phase of the study at fixed intervals, the disease has not progressed in over ten months.

Immunological principle proven in an exemplary manner
With the evaluation of immunological data it was possible to prove in an exemplary manner that those patients that completed the entire planned three-month treatment cycle with MGN1601 in accordance with the study protocol have generated a clear immune response. The strength of the immune response increased with continued treatment. With these results, the mechanism of action demonstrated in preclinical studies could also be confirmed in patients. In the view of MOLOGEN AG, the observed positive effects with respect to overall survival can thus be attributed to the treatment with MGN1601.

Concurrently to the evaluation of the study, MOLOGEN has also applied for scientific advice at the Paul-Ehrlich-Institut, to discuss, amongst others, questions relating to the design of future clinical studies. Subsequent clinical studies with MGN1601 will then be applied for.

Prof. Dr. Burghardt Wittig, Chairman of the Scientific Advisory Board of MOLOGEN AG, states: "As a scientist, I am delighted that our molecular biological and immunological concepts for active therapeutic vaccination against cancer were able to prove their efficacy so impressively with MGN1601. I find it particularly noteworthy that we were now able to clearly show what we had hitherto only been able to assume: active immunotherapies against cancer, like MGN1601, need time before they can show their effect. Tragically, all patients for whom the therapy with MGN1601 came too late have already died, while all other patients - apart from one, who survived for more than eleven months - are still alive today."

Dr. Matthias Schroff, Chief Executive Officer at MOLOGEN AG, adds: "It is a very positive surprise that our second oncological product candidate MGN1601 is already showing such excellent efficacy data in phase I/II. Thereby, our product pipeline has taken a great step forward. For this reason I am very confident with regard to our further clinical studies, both for MGN1703, our immunomodulator, which we are applying in the field of colorectal cancer and lung cancer, and also for MGN1601, our renal cancer therapy."

Presentation at the annual congress of the American Association for Cancer Research
MOLOGEN project manager Ekaterina Weith is to present the data together with Prof. Dr. Burghardt Wittig (Chairman of the Scientific Advisory Board of MOLOGEN AG) at the annual meeting of the American Association for Cancer Research (AACR) as part of a "Late-Breaking Poster Session" on April 3, 2012 in Chicago, USA (poster no. LB-233). The AACR is the world's oldest and largest scientific organization that is dedicated to all aspects of high-quality, innovative cancer research.

About the phase I/II clinical study (ASET study)
Within the framework of the ASET study, patients receive a total of eight treatments with MGN1601 over a period of twelve weeks. The patients are examined after completion of the treatment phase. If the patients have at least responded to the treatment with stabilization of the originally progressing cancer disease after twelve weeks, they can be treated further within an extension phase. In this extension phase, the patients receive up to five further treatments distributed over two years at increasing intervals. As reported, patient recruitment was finalized ahead of schedule after acceptance of 19 patients into the study, since it had already been possible to achieve the primary goal of the study, namely to verify the safety and tolerability of the compound.

About MGN1601
The tumor therapy with MGN1601 is a therapeutic vaccination to fight advanced renal cancer and to prevent their recurrence after operation and medical treatment.

MGN1601 is a cell-based cancer therapy based on genetically modified tumor cells. A cell bank established by MOLOGEN AG from human renal cancer cells in accordance with pharmaceutical regulations forms the basis. These cancer cells from the cell bank, foreign (allogeneic) to the patient, are "genetically modified" with additional genetic information with the help of four different MIDGE® vectors developed by MOLOGEN and are combined with the DNA immunomodulator dSLIM®, also developed by MOLOGEN, as an adjuvant.

The active principle of the cell-based gene therapy involves induction of a cross-reaction of the patient's immune system against their own cancer cells after the immune system has learned what cancer cells typically look like via its response to the genetically-modified foreign cancer cells.

About renal cancer
Renal cancer is the most frequently occurring malignant tumor of the kidneys with 200,000 incidences annually throughout the world. According to the Robert Koch Institute, there are 15,000 patients affected by this disease in Germany alone. Among these patients, around 30% already have distant metastases at the time of initial diagnosis, which significantly reduces the success of a therapy. The tumor is known for not responding to radiation or chemotherapy. The use of medications which are currently available on the market are accompanied by considerable side effects. Thus there is still a great medical need for new, effective medications with low side effects for the treatment of renal cancer. Exactly this approach is followed with MGN1601.

Orphan Drug Status
The cell-based gene therapy against renal cancer has received the Orphan Drug Status from the European Medical Agency (EMA). This enables MOLOGEN AG to market the product exclusively within the European Union within a period of ten years. The Orphan Drug Program of the European Union is supposed to promote the development of therapies for rare and serious diseases.

About MOLOGEN AG
MOLOGEN AG, a German biopharmaceutical company with headquarters in Berlin specializes in the research and development of innovative medications on the basis of DNA structures. The activities focus on numerous product developments which are relevant to the immune system; on the one hand vaccines against infectious diseases and on the other hand cancer medications. MOLOGEN AG is globally one of the few biotechnology companies with well tolerated DNA-based cancer treatment in the clinical development phase.

The stocks of MOLOGEN AG are listed in the Prime Standard of the German stock exchange (ISIN DE0006637200).

Memberships in associations:
Biotechnologieverbund Berlin-Brandenburg (bbb) e.V. | BIO Deutschland e.V. | DECHEMA - Society for chemical technology and biotechnology e.V. | German industrial association of biotechnology (DIB) | Association for the Promotion of Science and Humanities in Germany | Association of German biotechnology companies (VBU) | Association of researching manufacturers of pharmaceuticals e.V. (VFA) | Association of the chemical industry e.V. (VCI)

MIDGE®, dSLIM® and MOLOGEN® are registered trademarks of MOLOGEN AG.

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Canadian Urological Association (CUA)

65^th Annual Meeting

June 27 - 29, 2010

Delta Prince Edward Hotel
Charlottetown, PEI Canada

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Prof Eoin O'Brien

Prof Eoin O’Brien explains that the technique of renal denervation is a promising cardiovascular intervention but it should still be used with caution for the moment.

Few techniques have excited cardiovascular medicine as much as renal denervation. There have been a limited number of publications providing promising but scant evidence, and meetings and prospective trials are being organised in many countries.

The technique has been hailed as a cure for hypertension and doctors with interventional skills have been quick to offer the procedure to patients willing to pay the very high price for the procedure. Those professing a special interest in hypertension have been more circumspect and it is timely therefore to review the evidence and reappraise renal denervation.

In simple terms, renal denervation is cutting the sympathetic nerve supply to the kidney in the renal arteries and this has the effect of lowering blood pressure, as was achieved in the past with the more radical operation of abdominal sympathectomy.

Percutaneous transluminal radiofrequency sympathetic denervation of the renal artery (to give the technique its full appellation) consists of passing a catheter via the femoral artery into both renal arteries of a sedated patient under fluoroscopic screening.

Radiofrequency energy
Radiofrequency energy is then applied to disrupt the sympathetic nerve fibres so as to interrupt both local and central neurogenic reflexes that have a major role in the regulation of blood pressure (BP) through sodium reabsorption, renin production and renal blood flow.

The pain that is caused by denervation is an indication that the sympathetic fibres have been successfully ablated.

The National Institute for Health and Clinical Excellence (NICE) has reviewed the evidence of the procedure in over 300 patients. In the largest randomised control trial to date (the SIMPLICITY Study) in over 100 patients with resistant hypertension (BP greater than 160mmHg on three or more antihypertensive drugs), there was a reduction in 24-hour average blood pressure in the renal denervation group of 11/7mmHg, compared to a decrease of 3/1mmHg for the control group, with drug treatment being unchanged in both groups.

The long-term efficacy of the technique is not known, with follow-up only extending to about two years in treated patients.

Apart from peri-procedural loin, or para-umbilical pain, which can be effectively managed with opioid analgesia and sedation, major complications from the procedure have been infrequent. But renal artery dissection, pseudoaneurysm, haematoma, renal artery dissection and renal artery perforation, transient ischaemic attacks, angina requiring stenting, hypertensive crisis and hypotension have been reported.

Possible long-term effects, which are theoretical and will only become evident with time, are late stenosis of the renal artery, renal artery infarction, promotion of atheromatous disease in the renal artery, other renal artery damage, sodium depletion and hypotension.

Recommendations for clinical use
The Joint UK Societies’ Consensus Statement on Renal Denervation for Resistant Hypertension has recently been published on behalf of the British Hypertension Society, the British Cardiovascular Intervention Society, the British Society for Interventional Radiology, the National Institute for Clinical Outcomes Research, the British Cardiovascular Society and the Renal Association, with guidance and advice from patients who had undergone this procedure.

The statement recommends that the following criteria should be observed:
•    Patients with resistant hypertension: the technique should be used only in patients with resistant hypertension, defined as a sustained clinic systolic blood pressure of ?160mmHg (?150mmHg in type II diabetes) in patients on three or more anti-hypertensive medications. Resistance to therapy should be confirmed using 24-hour ambulatory blood pressure monitoring (ABPM) that is of sufficient quality to provide at least 14 daytime readings that must average more than 150mmHg. The use of ABPM is essential so as to allow detection of a ‘white-coat’, or alerting, response, which may be a cause of apparently resistant hypertension.

It is important to note that the term ‘resistant hypertension’ may include individuals who are truly resistant (with or without secondary causes); those who are pseudo-resistant, such as those who may be non-concordant with medication, or who may be intolerant of medication; and those taking other medications that may be contributing to their resistant hypertension.
•    Exclusion of secondary hypertension: comprehensive exclusion of secondary causes of hypertension is mandatory prior to renal denervation. Even if a careful history and evaluation have been previously undertaken when hypertension was first diagnosed, the sudden emergence of resistant hypertension in a patient previously well controlled may signal a new secondary cause on a background of previous primary hypertension.

Renal denervation should not be used to treat resistant hypertension due to a secondary cause where a known alternative remedy exists.

Renal denervation should not be used to treat resistant hypertension due to a secondary cause where a known alternative remedy exists.
•    Selection of patients: the selection, treatment and follow-up of patients should be conducted by a multidisciplinary team, which must include hypertension specialists who can demonstrate active involvement in the routine investigation and care of patients with resistant hypertension. The European Society of Hypertension provides strict criteria for accreditation as a hypertension specialist.

The team should also include interventional cardiologists and/or radiologists and renal specialist advice should also be available. A written protocol for the renal denervation procedure, including contingency plans for the management of any complications, should be available.
•    Renal considerations: patients must be shown to have suitable renal artery anatomy — usually one main renal artery to each kidney >20mm in length and >4mm in diameter without significant stenosis or other abnormality.
•    Performance of the procedure: only interventional cardiologists or radiologists who have been trained in the procedure and are competent to manage complications such as dissection of the renal artery should undertake the intervention.
•    Patient information: patients should be given a clear description of the procedure, including provision of contemporary statistics on success rates/potential complications, detailed technical information regarding the procedure itself and aftercare. Patients must also give written and verbal consent to treatment. A patient information leaflet is available from NICE.
•    National Registry for Renal Denervation: data on all patients undergoing this procedure in the UK must be submitted to a national registry to inform practice, generate research opportunities and permit audit of clinical effectiveness.

Conclusion
Percutaneous renal sympathetic denervation is undoubtedly a most promising cardiovascular intervention. It may be that ongoing and future trials will prove it to be the treatment of choice for patients with resistant hypertension, or even a substitute for, or adjunct to, life-long drug treatment in many patients.

But we are far from being able to make any definitive conclusions, other than to say that the technique appears to be effective in lowering blood pressure in resistant hypertension in the short term and that it has relatively few immediate complications.

The recommendations of NICE1 and the Joint UK Societies2 on the use of the technique in clinical practice are to be welcomed. They should serve as guidance to specialists wishing to make the technique available, especially in relation to the need for a multidisciplinary approach so as to remove the decision for intervention from the operator.

These recommendations also provide guidance for healthcare providers faced with deciding if the high cost of the technique is justified. Most importantly, they provide information for patients for whom renal denervation is recommended.

References on request.

Prof Eoin O’Brien is Professor of Molecular Pharmacology at the Conway Institute, University College Dublin.

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By JUAN A. LOZANO

LUFKIN, Texas

The fate of a Texas nurse accused of killing five kidney dialysis patients by injecting them with bleach could soon be in a jury's hands.

Closing arguments are set for Thursday in the capital murder trial of Kimberly Clark Saenz. Prosecutors allege Saenz caused the five patients' deaths in April 2008 at a clinic in the East Texas city of Lufkin by injecting bleach into their dialysis lines. Two patients told jurors they saw Saenz use syringes to draw bleach from a cleaning pail and inject it into the IV lines of two other patients.

Saenz's attorney, Ryan Deaton, argued she was made a scapegoat for faulty procedures, including improper water purification, at the DaVita Dialysis clinic about 125 miles northeast of Houston. Deaton also suggested clinic officials have fabricated evidence against Saenz.

The 38-year-old Saenz faces a possible death sentence if convicted of capital murder. Her trial, in its fourth week, began March 5.

She didn't take the stand in her own defense but in a recording played at trial, the former nurse can be heard testifying before a grand jury that she felt "railroaded" by the clinic and "would never inject bleach into a patient."

Saenz is charged with one capital murder count that accuses her of killing as many as five patients. She's also charged with five counts of aggravated assault for injuries to five other patients.

Investigators testified they found Internet searches on Saenz's computer about bleach poisoning in blood and whether bleach could be detected in dialysis lines.

Bleach is commonly used to disinfect plastic lines and other dialysis equipment at the clinic. Saenz's attorneys said she was spotted measuring bleach into a syringe because she wanted to put the right amount into cleaning water.

Former DaVita employees who testified for prosecutors told jurors they never used syringes instead of measuring cups to ensure the proper amounts of bleach were being used in cleaning solutions. Dialysis patients spend up to three days a week tethered for hours to a machine that filters their blood because their kidneys can't.

Saenz was charged a year after the clinic was closed for about two months in the wake of a rash of illnesses and deaths in April 2008.

Emergency crews had been called to the clinic as many as 30 times that April and made at least 19 runs. Seven of the calls were for cardiac problems.

There had been only two calls during the previous 15 months, according to the Texas Department of Health Services.

Denver-based health care giant DaVita Inc. investigated along with local, state and federal agencies.

A Food and Drug Administration report found some samples linked to some victims tested positive for bleach while others showed bleach "may have been present at one time."

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