Pharma News

[GodFather]

GSK announces US submission for dabrafenib/trametinib combination in metastatic melanoma

GlaxoSmithKline (GSK) plc has announced submission of supplemental New Drug Applications (NDAs) to the US Food and Drug Administration for use of dabrafenib, a BRAF inhibitor, in combination with trametinib, a MEK inhibitor. Supplemental applications were submitted to each of the currently approved NDAs for the use of each drug in combination with the other, for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 E or K mutation.

The applications are based on data from a randomised Phase I/II study comparing dabrafenib monotherapy to combination therapy with dabrafenib and trametinib in patients with BRAF V600E and V600K mutation positive metastatic melanoma.

Use of dabrafenib and trametinib in combination is investigational and not approved anywhere in the world. European review of the MAA submission for trametinib, both as monotherapy and in combination with dabrafenib, is ongoing. CHMP has reverted from the accelerated assessment review process to standard timelines to allow sufficient time for review of the submission.

GlaxoSmithKline - one of the world's leading research-based pharmaceutical and healthcare companies - is committed to improving the quality of human life by enabling people to do more, feel better and live longer.


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[GodFather]

Antiviral enzyme contributes to several forms of cancer

Researchers at the University of Minnesota have discovered that a human antiviral enzyme causes DNA mutations that lead to several forms of cancer. The discovery, reported in the July 14 issue of Nature Genetics, follows the team's earlier finding that the enzyme, called APOBEC3B, is responsible for more than half of breast cancer cases. The previous study was published in Nature in February.

APOBEC3B is part of a family of antiviral proteins that Harris has studied for more than a decade. His effort to understand how these proteins work has led to these surprising discoveries that APOBEC3B is a broadly important cancer mutagen.

"We are very excited about this discovery because it indicates that a single enzyme is one of the largest known contributors to cancer mutation, possibly even eclipsing sources such as UV rays from the sun and chemicals from smoking," says Reuben Harris, a professor of biochemistry, molecular biology and biophysics based in the College of Biological Sciences. Harris, who led the study, is also a member of the Masonic Cancer Center, University of Minnesota.

For the current study, Harris, along with colleagues Michael Burns and Alpay Temiz, analyzed tumor samples from 19 different types of cancer for the presence of APOBEC3B and 10 related proteins. Results showed that APOBEC3B alone was significantly elevated in six types (bladder, cervix, two forms of lung cancer, head & neck, and breast). Levels of the enzyme, which is present in low levels in most healthy tissues, were elevated in several other types of cancer as well.

A second key finding was that the mutational signature of APOBEC3B is a close match to the actual mutation pattern in these cancers. "Much like we each have unique written signatures, these enzymes each leave a unique mark," Harris says.

Findings from both studies are counter-intuitive because the enzyme, which is produced by the immune system, is supposed to protect cells from HIV and other viruses, not harm our own genomic DNA.

While it's well known that sunlight and chemical carcinogens can mutate DNA, and that mutations are essential for cancer to develop, Harris is the first to discover that this human enzyme is a major cause mutation in cancer. He believes that APOBEC3B is a biological "double-edged sword" that protects some cells from viruses such as HIV and produces mutations that give rise to cancer in others.

Harris hopes to find a way to block APOBEC3B from mutating DNA, just as sunscreen blocks mutations that lead to melanoma. Many cancer mutations have been identified, but discovering a common source of mutation such as APOBEC3B is expected to help researchers to move "upstream" and look for a way to stop carcinogenesis closer to its source, he says, "like damming a river before it wreaks havoc on downstream areas." It's also possible that a simple test for APOBEC3B could be used to detect cancer earlier.

Harris is a professor in the Department of Biochemistry, Molecular Biology and Biophysics, which is a joint department of the College of Biological Sciences and the Medical School. He is also a member of the Masonic Cancer Center, University of Minnesota, which is part of the National Cancer Institute's network of Comprehensive Cancer Centers. Harris and colleagues are grateful for support from the National Institutes of Health, the Department of Defense Breast Cancer Research Program, the Jimmy V Foundation, and the Minnesota Ovarian Cancer Alliance.

[GodFather]

Benefits of Pradaxa® maintained in difficult to treat patients with atrial fibrillation and symptomatic heart failure

Published in the European Journal of Heart Failure1, results from a new sub-analysis of the RE-LY®* trial demonstrate important benefits of Pradaxa® (dabigatran etexilate) over warfarin in difficult-to-treat patients with non-valvular atrial fibrillation (AF) and previous symptomatic heart failure (HF). The outcomes in heart failure patients were consistent with the results from the main RE-LY® trial: Pradaxa® 150mg twice daily reduced the risk of stroke including ischaemic stroke with similar rates of major bleeding compared to warfarin and Pradaxa® 110mg twice daily showed similar rates of stroke but significantly reduced major bleeding compared to warfarin. Importantly, both doses of Pradaxa® significantly reduced intracranial as well as total bleeding.(1,2,3)

The new results support that Pradaxa® can also be beneficial for patients with multiple co-morbidities and further reinforce the consistent efficacy and safety profile of Pradaxa® that was shown in the main trial and various previous RE-LY® sub-analyses in several other patient subgroups, including patients with type 2 diabetes.(4-8)

"Atrial fibrillation and heart failure frequently coexist and are known to worsen patient prognoses. Heart failure is a specific risk factor for stroke in atrial fibrillation patients, therefore these patients especially need anticoagulant treatment," said Dr. Jorge Ferreira, Cardiologist, Hospital Santa Cruz, Lisbon, Portugal. "However, anticoagulation with a vitamin-K-antagonist in these patients is often associated with poor INR control. This results in more challenging management and impacts the overall efficacy and safety of VKA treatment."

From a total of 18,113 patients with non-valvular AF participating in the landmark RE-LY® trial, 4,904 patients (27%) had previous symptomatic HF.(2,3) In the sub-analysis comparing the main outcomes of stroke and systemic embolism as well as major bleeding between patients with and without previous symptomatic heart failure, the results were consistent with no statistically significant differences (p-values for interaction) between the two patient groups.(1) These results show that Pradaxa® is a valuable treatment alternative for patients who suffer from both atrial fibrillation and heart failure.

"These new results from RE-LY® highlight the value of Pradaxa® also for those atrial fibrillation patients that are traditionally considered difficult to treat and have multiple co-morbidities," commented Professor Klaus Dugi, Corporate Senior Vice President Medicine, Boehringer Ingelheim.

Pradaxa® 150mg bid is the only novel oral anticoagulant, study of which has shown a significant reduction in the incidence of ischaemic strokes in patients with non-valvular AF compared to warfarin (67% median time in therapeutic range9), offering a relative risk reduction of 25%.2,3 Nine out of ten strokes in AF patients are ischemic strokes,(10) which can result in irreversible neurological injury with profound long-term consequences such as paralysis or inability to move one's limbs or formulate speech.(11)

Furthermore in the main RE-LY® trial, Pradaxa® 150mg twice daily provided a 36% reduction in the overall risk of stroke versus warfarin, demonstrating superior protection.(2,3) Pradaxa® 110mg twice daily, indicated for certain patients, was as effective as warfarin for the prevention of stroke and systemic embolism.(2,3) Both doses of Pradaxa® were associated with significantly lower total, intracranial and life-threatening bleeding compared to warfarin.(2,3) Pradaxa® 150mg twice daily showed a similar risk of major bleeds versus warfarin while Pradaxa® 110mg twice daily demonstrated a significantly lower risk.(2,3) The RE-LY® trial was performed in PROBE design, i.e. prospective, randomized, open-label with blinded endpoint evaluation.

Pradaxa® is already widely approved for the prevention of stroke and systemic embolism in patient with non-valvular atrial fibrillation and for primary prevention of VTE following total hip replacement or total knee replacement surgery.(9) Over 1.6 million patient years of experience in all licensed indications in over 100 countries support Pradaxa® as the leading novel oral anticoagulant.(12)

About Pradaxa® (dabigatran etexilate)
Pradaxa® is approved in over 100 countries worldwide.(12) It is licensed for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation and for the primary prevention of venous thromboembolism in patients undergoing total hip replacement or total knee replacement surgery.(9)

Pradaxa®, a direct thrombin inhibitor (DTI),13 was the first of a new generation of direct oral anticoagulants targeting a high unmet medical need in the prevention and treatment of acute and chronic thromboembolic diseases.

Potent antithrombotic effects are achieved with direct thrombin inhibitors by specifically blocking the activity of thrombin (both free and clot-bound), the central enzyme in the process responsible for clot (thrombus) formation. In contrast to vitamin-K antagonists, which variably act via different coagulation factors, dabigatran etexilate provides effective, predictable and consistent anticoagulation with a low potential for drug-drug interactions and no drug-food interactions, without the need for routine coagulation monitoring or dose adjustment.

About RE-LY®
RE-LY® (Randomized Evaluation of Long term anticoagulant therapY) was a global, phase III, PROBE (prospective, randomized, open-label with blinded endpoint evaluation) trial of 18,113 patients enrolled in over 900 centres in 44 countries designed to compare two fixed doses of the oral direct thrombin inhibitor dabigatran (110mg and 150mg twice daily) each administered in a blinded manner, with open label warfarin (INR 2.0-3.0, median TTR 67%9).(2,3) Patients were followed-up in the study for a median of 2 years with a minimum of 1 year follow-up.(2)

The primary endpoint of the trial was incidence of stroke (including haemorrhagic) or systemic embolism. Secondary outcome measures included all-cause death, incidence of stroke (including haemorrhagic), systemic embolism, pulmonary embolism, acute myocardial infarction, and vascular death (including death from bleeding).(2,3)

Compared to warfarin, dabigatran etexilate showed in the trial:(2,3)

Significant reduction in the risk of stroke and systemic embolism - including ischaemic strokes with dabigatran etexilate 150mg twice daily
Similar rates of stroke/systemic embolism with dabigatran etexilate 110mg twice daily (110mg indicated for certain patients)
Significantly lower major bleeding events with dabigatran etexilate 110mg twice daily
Significantly lower life threatening and intracranial bleeding with both doses
Significant reduction in vascular mortality with dabigatran etexilate 150mg twice daily.

About the new RE-LY® sub-analysis
From a total of 18,113 patients with non-valvular AF participating in the landmark RE-LY® trial, 4,904 patients (27%) had previous symptomatic HF.(2,3) Despite the challenges of VKA therapy in these patients, the heart failure patients included in the RE-LY® trial spent 63.8% of their time within the therapeutic range (INR 2.0-3.0).(1) In the sub-analysis, the results were consistent between patients with and without HF, showing that Pradaxa® is a valuable treatment alternative for patients with AF and HF:(1)

Annual rates of stroke and systemic embolism were 1.44% per year for Pradaxa® 150mg twice daily and 1.90% per year for Pradaxa® 110mg twice daily versus 1.92% per year for warfarin
Annual rates of major bleeding were 3.10% per year for Pradaxa® 150mg twice daily and 3.26% per year for Pradaxa® 110mg twice daily versus 3.90% per year for warfarin
Rates of intracranial haemorrhage, one of the most devastating complications of anticoagulation,14 were 0.26% per year for Pradaxa® 150mg twice daily and 0.22% per year for Pradaxa® 110mg twice daily versus 0.65% per year for warfarin

Stroke Prevention in Atrial Fibrillation (AF)
AF is the most common sustained heart rhythm condition,(15) with one in four adults over the age of 4015 developing the condition in their lifetime. People with AF are more likely to experience blood clots, which increases the risk of stroke by five-fold.(16) Up to three million people worldwide suffer strokes related to AF each year.(17,18) Strokes due to AF tend to be severe, with an increased likelihood of death (20%), and disability (60%).(19)

Ischaemic strokes are the most common type of AF-related stroke, accounting for 92% of strokes and frequently leading to severe debilitation.(10) Appropriate anticoagulation therapy can help to prevent many types of AF-related strokes and improve overall patient outcomes.(20) Pradaxa® 150mg twice daily is the only novel oral anticoagulant, for which its pivotal trial vs. warfarin has shown a statistically significant and clinically relevant reduction of both ischaemic and haemorrhagic strokes.(2,3) Additionally, treatment with Pradaxa® is associated with substantially lower rates of both fatal and non-fatal intracranial haemorrhage, one of the most devastating complications of anticoagulation therapy.(14,21)

Worldwide, AF is an extremely costly public health problem, with treatment costs equating to $6.65 billion in the US and over €6.2 billion across Europe each year.(22,23) Given AF-related strokes tend to be more severe, this results in higher direct medical patient costs annually.(24) The total societal burden of AF-related stroke reaches €13.5 billion per year in the European Union alone.(25)

About Boehringer Ingelheim
The Boehringer Ingelheim group is one of the world's 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 140 affiliates and more than 46,000 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel medications of high therapeutic value for human and veterinary medicine.

As a central element of its culture, Boehringer Ingelheim pledges to act socially responsible. Involvement in social projects, caring for employees and their families, and providing equal opportunities for all employees form the foundation of the global operations. Mutual cooperation and respect, as well as environmental protection and sustainability are intrinsic factors in all of Boehringer Ingelheim's endeavors.

In 2012, Boehringer Ingelheim achieved net sales of about 14.7 billion euro. R&D expenditure in the business area Prescription Medicines corresponds to 22.5% of its net sales.

1. Ferreira J, et al. Dabigatran compared with warfarin in patients with atrial fibrillation and symptomatic heart failure: a subgroup analysis of the RE-LY trial. Eur J of Heart Failure. 2013; doi 10.1093/eurjhf/hft111.
2. Connolly SJ, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-51.
3. Connolly SJ, et al. Newly identified events in the RE-LY trial. N Engl J Med. 2010;363:1875-6.
4. Diener HC, et al. Dabigatran compared with warfarin in patients with atrial fibrillation and previous transient ischaemic attack or stroke: a subgroup analysis of the RE-LY trial. Lancet Neurology. 2010;9:1157–1163.
5. Wallentin L, et al. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet. 2010;376:975–983.
6. Eikelboom JW, et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial. Circulation. 2011;123:2363–2372.
7. Oldgren J, et al. Risks for stroke, bleeding, and death in patients with atrial fibrillation receiving dabigatran or warfarin in relation to the CHADS2 score: a subgroup analysis of the RE-LY trial. Ann Intern Med. 2012;155:660–668.
8. Darius H, et al. Comparison of Dabigatran versus Warfarin in Diabetic Patients with Atrial Fibrillation: Results from the RE-LY Trial. Presented at the American Heart Association's Scientific Sessions 2012, Los Angeles, USA. Abstract No. 15937.
9. Pradaxa European Summary of Product Characteristics, 2013
10. Andersen KK, et al. Hemorrhagic and ischemic strokes compared: stroke severity, mortality, and risk factors. Stroke. 2009;40:2068−72.
11. NHLBI website. “What is Stroke?” Available at: www.nhlbi.nih.gov/health/health-topics/topics/stroke. Accessed on: October 10, 2012.
12. Boehringer Ingelheim data on file.
13. Di Nisio M, et al. Direct thrombin inhibitors. N Engl J Med 2005; 353:1028-40.
14. Hart RG, et al. Intracranial hemorrhage in atrial fibrillation patients during anticoagulation with Warfarin or Dabigatran: The RE-LY® Trial. Stroke. 2012;43(6):1511-1517.
15. Lloyd-Jones DM, et al. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation. 2004;110:1042-6.
16. Camm JA, et al. 2012 focused update of the ESC guidelines for the management of atrial fibrillation. Eur Heart J. 2012;33:2719-47.
17. Camm JA, et al. Guidelines for the management of atrial fibrillation. European Heart Journal .2010;31:2369–2429.
18. Atlas of Heart Disease and Stroke, World Health Organization, September 2004. Viewed Nov 2012 at www.who.int/cardiovascular_diseases/en/cvd_atlas_15_burden_stroke.pdf
19. Gladstone DJ, et al. Potentially Preventable Strokes in High-Risk Patients With Atrial Fibrillation Who Are Not Adequately Anticoagulated. Stroke. 2009;40:235-240.
20. Aguilar MI, Hart R. Oral anticoagulants for preventing stroke in patients with non-valvular atrial fibrillation and no previous history of stroke or transient ischemic attacks. Cochrane Database of Systematic Reviews. 2005, Issue 3. Art. No.: CD001927.
21. Fang MC, et al. Death and disability from warfarin-associated intracranial and extracranial hemorrhages. Am J Med. 2007; 120:700 –705.
22. Coyne KS, et al. Assessing the direct costs of treating nonvalvular atrial fibrillation in the United States. Value Health 2006; 9:348-56.
23. Ringborg A, et al. Costs of atrial fibrillation in five European countries: results from the Euro Heart Survey on atrial fibrillation. Europace 2008; 10:403-11.
24. Brüggenjürgen B, et al. The impact of atrial fibrillation on the cost of stroke: the Berlin acute stroke study. Value Health 2007;10:137-43.
25. Fuster V, et al. ACC/AHA/ESC 2006 Guidelines for the management of patients with atrial fibrillation – executive summary. Circulation. 2006;114:700-52.

*RE-LY® was a PROBE trial (prospective, randomized, open-label with blinded endpoint evaluation), comparing two fixed doses of the oral direct thrombin inhibitor dabigatran etexilate (110 mg bid and 150 mg bid) each administered in a blinded manner, with open label warfarin.(2,3)

[GodFather]

Physicists offer novel insight into experimental cancer treatment

Physicists from the University of York have carried out new research into how the heating effect of an experimental cancer treatment works. Magnetic hyperthermia is viewed as an attractive approach for the treatment of certain cancers as it has no known side effects compared to more conventional therapies such as chemotherapy. It is particularly suitable for the treatment of prostate cancer and brain tumours. However, until now there has been no clear theoretical understanding of how it actually works.

Treatment by magnetic hyperthermia involves injecting magnetic nanoparticles directly into a tumour then placing the patient in a machine which produces an alternating magnetic field. The nanoparticles oscillate and heat is produced inside the tumour tissue. When the temperature rises above 42ºC cells begin to die. This heating process has been demonstrated to reduce tumour size.

The study, by researchers from the University of York's Department of Physics and Liquids Research Ltd, of Bangor, North Wales, showed that the amount of heat generated by magnetic nanoparticles can be understood when both the physical and hydrodynamic size distributions for the samples are known to high accuracy.

The results of the study are published in the Journal of Physics D: Applied Physics as a fast track communication.

Lead author Dr Gonzalo Vallejo-Fernandez, from York's Department of Physics, said: "While clinical trials have shown the potential of magnetic nanoparticles for cancer treatment, the mechanisms by which the heat is generated have not been fully understood. This understanding is critical to produce particles with optimised properties for specific applications at minimal dose."

Previously the heat generated was impossible to predict as several mechanisms were involved. The new work has identified and quantified the mechanisms so that work can now begin to determine the dosage required for effective treatment.

Dr Vallejo-Fernandez said: "Through our study we have produced the first comprehensive assessment of how the heating effect in magnetic hyperthermia works. We are now in a position where we can do further work to calculate accurately the dose of magnetic nanoparticles and length of treatment required."

For the study, the researchers used magnetic nanoparticles produced by a new technique by Liquids Research Ltd, which was developed under the EU project MULTIFUN (Multifunctional Nanotechnology for Selective Detection and Treatment of Cancer). The nanoparticles are very uniform in size and well separated, which enabled detailed experiments to be performed which broadly confirmed the accuracy of the calculations.

Dr Vijay Patel, Director of Liquids Research Ltd, said: "The development of this new theory coincided with our work on the new process to fabricate the nanoparticles enabling us to 'design' almost ideal particles for this application."

[GodFather]

Uncovering a healthier remedy for chronic pain

Physicians and patients who are wary of addiction to pain medication and opioids may soon have a healthier and more natural alternative. A Duke University study revealed that a derivative of DHA (docosahexaenoic acid), a main ingredient of over-the-counter fish oil supplements, can sooth and prevent neuropathic pain caused by injuries to the sensory system. The results appear online in the Annals of Neurology.

The research focused on a compound called neuroprotectin D1=protectin D1 (NPD1=PD1), a bioactive lipid produced by cells in response to external stimuli. NPD1=PD1 is present in human white blood cells, and was first identified based on its ability to resolve abdominal and brain inflammation.

"These compounds are derived from omega-3 fatty acids found in fish oil, but are 1,000 times more potent than their precursors in reducing inflammation," said Ru-Rong Ji, professor of anesthesiology and neurobiology at Duke University Medical Center and principal investigator of the study.

The team used laboratory mouse models of nerve injuries to simulate pain symptoms commonly associated with post-surgical nerve trauma. They treated these animals with chemically-synthesized NPD1=PD1, either through local administration or injection, to investigate whether the lipid compound could relieve these symptoms.

Their findings revealed that NPD1=PD1 not only alleviated the pain, but also reduced nerve swelling following the injuries. Its analgesic effect stems from the compound's ability to inhibit the production of cytokines and chemokines, which are small signaling molecules that attract inflammatory macrophages to the nerve cells. By preventing cytokine and chemokine production, the compound protected nerve cells from further damage. NPD1=PD1 also reduced neuron firing so the injured animals felt less pain.

Ji believes that the new discovery has clinical potential. "Chronic pain resulting from major medical procedures such as amputation, chest and breast surgery is a serious problem," he said. Current treatment options for neuropathic pain include gabapentin and various opioids, which may lead to addiction and destruction of the sensory nerves.

On the other hand, NPD1=PD1 can relieve neuropathic pain at very low doses and, more importantly, mice receiving the treatment did not show signs of physical dependence or enhanced tolerance toward the lipid compound.

"We hope to test this compound in clinical trials," Ji said. The initial stages of the trial could involve DHA administration through diet and injection. "DHA is very inexpensive, and can be converted to NPD1 by an aspirin-triggered pathway," he said. The ultimate goal is to develop a safer approach to managing chronic pain.

The research was supported by National Institutes of Health grants R01DE17794; R01DE22743; P01GM095467; R21NS082985; Transformative R01NS67686.

Neuroprotectin/Protectin D1 protects neuropathic pain in mice after nerve trauma
Zhen-Zhong Xu, Xing-Jun Liu, Temugin Berta, Chul-Kyu Park, Ning Lü, Charles N. Serhan and Ru-Rong Ji. Annals of Neurology, online May 18, 2013. DOI: 10.1002/ana.23928

[GodFather]

HIV used to cure 2 genetic diseases


The AIDS virus can be used to treat two severe hereditary diseases. After an Italian scientist's "stroke of genius" in 1996, and after years of promising results in the laboratory, double official recognition by one of the most important international scientific journals has now arrived. And six children from all over the world, after three years of treatment, are well and show significant benefits. The announcement was made in two studies published today in Science by researchers at the San Raffaele Telethon Institute for Gene Therapy (TIGET) in Milan, led by Luigi Naldini, demonstrating that gene therapy vectors derived from the HIV virus works against two severe genetic diseases, metachromatic leukodystrophy and Wiskott-Aldrich syndrome.

"Three years after the start of the clinical trial," says Naldini, "the results obtained from the first six patients are very encouraging: the therapy is not only safe, but also effective and able to change the clinical history of these severe diseases. After 15 years of effort and our successes in the laboratory, but frustration as well, it's really exciting to be able to give a concrete solution to the first patients," explains the director of TIGET.

At the origin of both diseases is a genetic defect that results in the deficiency of a protein essential for the organism in the early years of life. In the case of metachromatic leukodystrophy, which currently lacks any effective treatment, it is the nervous system to be affected: babies with this disease are apparently healthy at birth, but at some point they begin to gradually lose the cognitive and motor skills they have acquired, with no possibility of arresting the neurodegenerative process. Children with Wiskott-Aldrich syndrome, on the other hand, have a faulty immune system that makes them much more vulnerable than normal to the development of infections, autoimmune diseases and cancer, as well as having a defect in the platelets which causes frequent bleeding.

After the positive results obtained in the course of many years of study in the laboratory, researchers at the San Raffaele Telethon Institute in Milan tried to correct the genetic defect that causes these diseases with gene therapy. The technique consists in withdrawing hematopoietic stem cells from the bone marrow of the patient and introducing a corrected copy of the gene that is defective using viral vectors derived from HIV (which began to be developed in 1996, thanks to Luigi Naldini's work). Once re-injected into the body, the treated cells are able to restore the missing protein to key organs.

"In patients with Wiskott-Aldrich syndrome, blood cells are directly affected by the disease and the corrected stem cells replace the diseased cells creating a properly functioning immune system and normal platelets. Thanks to gene therapy, the children no longer have to face severe bleeding and infection. They can run, play and go to school," explains Alessandro Aiuti, coordinator of the clinical study on these patients and Head of Research of the Pediatric Clinic at TIGET. "In the case of metachromatic leukodystrophy, however," says Alessandra Biffi, who heads the other study, "the therapeutic mechanism is more sophisticated: the corrected hematopoietic cells reach the brain through the blood and release the correct protein that is 'gathered' there by the surrounding nerve cells. The winning card was to make engineered cells able to produce a quantity of protein much higher than normal, and thus effectively counteract the neurodegenerative process." Eugenio Montini, who coordinated the molecular analysis of patients' cells, adds, "Until now we have never seen a way to engineer stem cells using gene therapy that is as effective and safe as this one. These results pave the way for new therapies for other more common diseases."

Both trials, which involved a team of over 70 people including researchers and clinicians, began in the spring of 2010, and called for the participation of 16 patients in total, 6 suffering from Wiskott-Aldrich syndrome and 10 from metachromatic leukodystrophy. The results published in Science refer only to the first 6 patients (three from each study), i.e. those for whom sufficient time has passed after administration of the therapy to allow scientists to draw the first significant conclusions regarding its safety and efficacy. In total, the Telethon Foundation has invested 19 million Euro for research on these two diseases (11 on metachromatic leukodystrophy and 8 on Wiskott-Aldrich syndrome).

"These preliminary results are promising and confirm the effectiveness of our efforts, which we have sustained over the years with great conviction," says the general manager of Telethon, Francesca Pasinelli. "We can say that we have created a model in which the charity organization acts not only as a funding agency, but plays a primary role in managing the development of research to ensure that each step of the process leads to the final objective, which is to provide accessible therapy to patients. To this end, we also chose to contribute towards the creation of a dedicated clinical unit and to select an Italian partner such as MolMed for vector development and production."

For Maria Grazia Roncarolo, scientific director of the San Raffaele Institute and the woman who designed and led the preparatory studies of the clinical trials of therapy for Wiskott-Aldrich syndrome, "the results described in these two studies make me very proud, both as scientific director and as pediatrician who has dedicated her entire professional life to children affected by genetic diseases. These goals are an example of how research conducted with accuracy, determination and total commitment can produce the desired results and lead to new frontiers in medicine. The translational path, from the bench in lab to the bedside of patients affected by Wiskott-Aldrich syndrome and metachromatic leukodystrophy, has also presented obstacles and frustrations, both for researchers and for parents and children who understandably find it hard to accept science 'slowness'. But the results we're showing today repay us of all the efforts and give us a great hope for the future of these children and for the possible cure of other genetic diseases".

"For years ago, when I was appointed president of Telethon - says Luca di Montezemolo - the two clinical trials at TIGET were about to start. It was a great scientific gamble and, overall, it represented an answer to the expectations of many families and patients. Today my first thought goes to them, to all those parents who contributed to our studies in the last years, although they knew research couldn't get there in time to save their own children. I also want to thank the scientists who achieved this extraordinary success and the million of Italians who have supported us with their donations".

Professor Gabriele Pelissero, Vice President of the San Raffaele Hospital concludes: "Once again our hospital proves to be a centre of excellence for the Italian healthcare system. We need to make these important realities grow in order to accept the challenge presented by the opening of the European healthcare boarders, so that we will be able to develop know-how, technologies and skills, to both continue treating Italian patients and attract patients from other countries as all the major European hospitals are about to do."

[GodFather]

Studies suggest new key to 'switching off' hypertension

A team of University of California, San Diego researchers has designed new compounds that mimic those naturally used by the body to regulate blood pressure. The most promising of them may literally be the key to controlling hypertension, switching off the signaling pathways that lead to the deadly condition.

Published online this month in Bioorganic & Medicinal Chemistry, the scientists studied the properties of the peptide called catestatin that binds nicotinic acetylcholine receptors found in the nervous system, and developed a pharmacophore model of its active centers. They next screened a library of compounds for molecules that might match this 3D "fingerprint". The scientists then took their in-silico findings and applied them to lab experiments, uncovering compounds that successfully lowered hypertension.

"This approach demonstrates the effectiveness of rational design of novel drug candidates," said lead author Igor F. Tsigelny, a research scientist with the university's San Diego Supercomputer Center (SDSC), as well as the UC San Diego Moores Cancer Center and the Department of Neurosciences.

"Our results suggest that analogs can be designed to match the action of catestatin, which the body uses to regulate blood pressure," said Daniel T. O'Connor, a professor at the UC San Diego School of Medicine and senior author of the study. "Those designer analogs could ultimately be used for treatment of hypertension or autonomic dysfunction."

The research may lead to a new class of treatments for hypertension, a disease which affects about 76 million people, or about one in three adults, in the United States, according to the American Heart Association. Untreated, it damages the blood vessels and is a leading risk factor for kidney failure, heart attack, and stroke.

Despite being a common and lethal cardiovascular risk factor, hypertension remains only partially controlled by current antihypertensive medications, most of which have serious side effects. Specifically, the SDSC/UC San Diego researchers targeted the hormone catestatin for therapeutic potential. Catestatin acts as the gatekeeper for the secretion of catecholamines - hormones that are released into the blood during times of physical or emotional stress. A drug that mimics the action of catestatin would thus allow people to control the hormones that regulate blood pressure.

Based on earlier studies of the structure of catestatin, O’Connor, Tsigelny, and their colleagues figured out which residues of catestatin are responsible for binding to the nicotinic receptor - similar to mapping how the ridges on a key fit into a lock. They created a three-dimensional model of the most important binding centers - the pharmacophore model. Then they screened about 250,000 3D compound structures in the Open NCI Database to select ones that fit this fingerprint of active centers. They discovered seven compounds that met the requirements, and tested those compounds in live cells to gauge their effects on catecholamines. Based on their findings, they tried one compound (TKO-10-18) on hypertensive mice, and showed that this compound produced the same anti-hypertensive effect as catestatin.

"Analysis of the catestatin molecule yielded a family of small organic compounds with preserved potency and pathway specificity," said Valentina Kouznetsova, PhD, an associate project scientist at SDSC and the UC San Diego Moores Cancer Center. "Further refinement of our model should lead to the synthesis and development of a novel class of antihypertensive agents."

Authors include SDSC's Tsigelny, O’Connor, and Kouznetsova, as well as Nilima Biswas and Sushil K. Mahata, of UC San Diego's Departments of Medicine and Pharmacology.

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Novartis delivered growth across all divisions in second quarter

Group net sales increased 1% (+3% cc) to USD 14.5 billion in the second quarter, with all divisions contributing to growth in constant currencies. Currency had a negative impact of 2 percentage points mainly from the weakening yen. Excluding the impact of patent expiries, underlying sales grew 8% in constant currencies. This performance was fueled by growth products such as Gilenya, Afinitor, Tasigna, Galvus, Xolair, the Q Family and Jakavi, which together contributed USD 4.5 billion or 31% of Group net sales, up 13% over the prior-year period. Generics impacted sales by approximately USD 0.8 billion, mainly due to Diovan and Zometa. Sales continued to benefit from the delayed entry of generic competition for Diovan monotherapy in the US.

Pharmaceuticals delivered net sales of USD 8.1 billion (-2%, +1% cc) in the second quarter, driven by strong volume growth (+10 percentage points), which offset the impact of generic competition (USD 0.7 billion, -9 percentage points). Pricing had a negligible impact. Growth products grew 26% (cc) to USD 3.0 billion, contributing 37% of division net sales compared to 30% in the same period last year.

Pharmaceuticals operating income decreased 7% (-3% cc) to USD 2.6 billion. Core operating income was USD 2.5 billion (-10%, -6% cc). Core operating income margin in constant currencies decreased by 2.3 percentage points; currency had a negative impact of 0.6 percentage points, resulting in a net decrease of 2.9 percentage points to 30.4% of net sales, mainly due to the impact of generic competition and continued investments in key projects in Specialty Care and Oncology.

Commenting on the results, Joseph Jimenez, CEO of Novartis, said: "Novartis delivered a solid second quarter, resulting in a good first half in 2013. Successful execution on growth brands allowed us to navigate patent expiries and new competition, while deepening our footprint in Emerging Growth Markets like China and Russia. Our underlying business showed strong growth behind significant innovation, with sales up 8% and core operating income up 17% in constant currencies in the first half excluding the impact of generics."

About Novartis
Novartis provides innovative healthcare solutions that address the evolving needs of patients and societies. Headquartered in Basel, Switzerland, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, eye care, cost-saving generic pharmaceuticals, preventive vaccines and diagnostic tools, over-the-counter and animal health products. Novartis is the only global company with leading positions in all these areas. In 2012, the Group achieved net sales of USD 56.7 billion, while R&D throughout the Group amounted to approximately USD 9.3 billion (USD 9.1 billion excluding impairment and amortization charges). Novartis Group companies employ approximately 129,000 full-time-equivalent associates and operate in more than 140 countries around the world.

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New plan of attack in cancer fight


New research conducted by Harvard scientists is laying out a road map to one of the holy grails of modern medicine: a cure for cancer. As described in a paper recently published in eLife, Martin Nowak, a professor of mathematics and of biology and director of the Program for Evolutionary Dynamics, and co-author Ivana Bozic, a postdoctoral fellow in mathematics, show that, under certain conditions, using two drugs in a "targeted therapy" - a treatment approach designed to interrupt cancer's ability to grow and spread - could effectively cure nearly all cancers.

Though the research is not a cure for cancer, Nowak said it does offer hope to researchers and patients alike.

"In some sense this is like the mathematics that allows us to calculate how to send a rocket to the moon, but it doesn't tell you how to build a rocket that goes to the moon," Nowak said. "What we found is that if you have a single point mutation in the genome that can give rise to resistance to both drugs at the same time, the game is over. We need to have combinations such that there is zero overlap between the drugs."

Importantly, Nowak said, for the two-drug combination to work, both drugs must be given together - an idea that runs counter to the way many clinicians treat cancer today.

"We actually have to work against the status quo somewhat," he said. "But we can show in our model that if you don’t give the drugs simultaneously, it guarantees treatment failure."

In earlier studies, Nowak and colleagues showed the importance of using multiple drugs. Though temporarily effective, single-drug targeted therapy will fail, the researchers revealed, because the disease eventually develops resistance to the treatment.

To determine if a two-drug combination would work, Nowak and Bozic turned to an expansive data set supplied by clinicians at New York's Memorial Sloan-Kettering Cancer Center that showed how patients respond to single-drug therapy. With data in hand, they were able to create computer models of how multidrug treatments would work. Using that model, they then treated a series of "virtual patients" to determine how the disease would react to the multidrug therapy.

"For a single-drug therapy, we know there are between 10 and 100 places in the genome that, if mutated, can give rise to resistance," Nowak explained. "So the first parameter we use when we make our calculations is that the first drug can be defeated by those possible mutations. The second drug can also be defeated by 10 to 100 mutations.

"If any of those mutations are the same, then it's a disaster," he continued. "If there's even a single mutation that can defeat both drugs, that is usually good enough for the cancer - it will become resistant, and treatment will fail. What this means is we have to develop drugs such that the cancer needs to make two independent steps - if we can do that, we have a good chance to contain it."

"You would expect to cure most patients with a two-drug combination," Bozic said. "In patients with a particularly large disease burden you might want to use a three-drug combination, but you would cure most with two drugs."

The trick now, Nowak and Bozic said, is to develop those drugs.

To avoid developing drugs that are not vulnerable to the same mutation, Bozic said, pharmaceutical companies have explored a number of strategies, including using different drugs to target different pathways in cancer's development.

"There are pharmaceutical companies here in Cambridge that are working to develop these drugs," Nowak said. "There may soon be as many as 100 therapies, which means there will be as many as 10,000 possible combinations, so we should have a good repertoire to choose from.

"I think we can be confident that, within 50 years, many cancer deaths will be prevented," Nowak added. "One hundred years ago, many people died from bacterial infections, and now they would be cured. Today, many people die from cancer, and we can't help them, but I think once we have these targeted therapies, we will be able to help many people - maybe not everyone - but many people."

Evolutionary dynamics of cancer in response to targeted combination therapy
Bozic I, Reiter JG, Allen B, Antal T, Chatterjee K, Shah P, Moon YS, Yaqubie A, Kelly N, Le DT, Lipson EJ, Chapman PB, Diaz LA Jr, Vogelstein B, Nowak MA
Elife. 2013 Jun 25;2:e00747. doi: 10.7554/eLife.00747

[GodFather]

FDA alerts companies to stop illegal sale of treatments for diabetes

The U.S. Food and Drug Administration is taking action to remove from the market illegal products, including some labeled as dietary supplements, that claim to mitigate, treat, cure or prevent diabetes and related complications. The agency recently issued letters warning 15 companies that the sale of their illegally marketed diabetes products violates federal law. The letters were sent to foreign and domestic companies whose products were sold online and in retail stores.

The FDA is advising consumers not to use these or similar products because they may contain harmful ingredients or may be otherwise unsafe, or may improperly be marketed as over-the-counter products when they should be marketed as prescription products. Using these products could cause consumers to delay seeking proper medical treatment for their diabetes. FDA-approved diabetes treatments, prescribed by a licensed health care professional and shown to be safe and effective, are readily available for people with diabetes.

"Diabetes is a serious chronic condition that should be properly managed using safe and effective FDA-approved treatments," said FDA Commissioner Margaret A. Hamburg, M.D. "Consumers who buy violative products that claim to be treatments are not only putting themselves at risk but also may not be seeking necessary medical attention, which could affect their diabetes management."

Nearly 26 million Americans have diabetes, a disease in which blood glucose or blood sugar levels are high, resulting from the body's inability to produce sufficient amounts of insulin or to effectively utilize its own insulin. There is a greater risk for serious health complications, such as heart disease, blindness, kidney failure, and lower-extremity amputations, if diabetes is not managed appropriately.

"The FDA is committed to protecting consumers from the dangers of these illegally sold products," said Howard Sklamberg, director of the Office of Compliance in the FDA's Center for Drug Evaluation and Research. "We will continue to take aggressive action against firms that sell illegal products claiming to treat diabetes."

Many of the illegally sold products that are the subject to this action include claims such as "prevents and treats diabetes," and "can replace medicine in the treatment of diabetes." In addition, some of the products may cause harm because the products contain undeclared active drug ingredients or may not have been manufactured and handled according to FDA quality standards.

These illegally sold products include:

Products sold as "natural" treatments for diabetes, but containing undeclared active pharmaceutical ingredients in unknown quantities that could cause harm or complicate medical conditions;
Dietary supplements and ayurvedic products (medicine of the healing arts that originated in India) with claims to treat, cure, and/or prevent diabetes;
Unapproved drugs sold over-the-counter, including some homeopathic products, intended to treat complications associated with diabetes, which include relieving symptoms caused by nerve damage in the arms and legs (also called peripheral neuropathy); and
Prescription drugs for diabetes sold by online pharmacies without a prescription.

The FDA has requested a written response from these companies within 15 business days stating how the companies will correct the violations. Failure to promptly correct the violations may result in legal action, including product seizure, injunction, and/or criminal prosecution.

To date, the FDA is not aware of any reports of injury or illness associated with the illegally sold products but is taking action to protect the public health from potential harm related to these violative products. The FDA asks health care professionals and consumers to report any adverse reactions to FDA's MedWatch program either by:

completing and submitting the report online at www.fda.gov/medwatch/report.htm; or
downloading and completing the form, then submitting it via fax at 1-800-FDA-0178.

About FDA
The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.