Pharma News

[GodFather]

Repurposed antidepressants have potential to treat small-cell lung cancer

A bioinformatics approach to repurposing drugs resulted in identification of a class of antidepressants as a potential new treatment for small-cell lung cancer (SCLC), according to a study published in Cancer Discovery, a journal of the American Association for Cancer Research.

Based on data generated using bioinformatics, two drugs approved by the U.S. Food and Drug Administration (FDA) to treat symptoms of depression were tested on SCLC cells and animal models. Both antidepressants were found to induce SCLC cell death. They were also effective in mice bearing human SCLCs that had become resistant to the chemotherapy drug cisplatin. The antidepressants tested were imipramine, which modulates the activity of certain hormones causing mood disorders; and promethazine, a sedative, antiemetic, and antipsychotic drug.

Bioinformatics is a combination of mathematics and computer science used to sort, classify, and analyze large databases of biological and biochemical information.

"We implemented a bioinformatics-based drug repositioning approach toward accelerated evaluation of FDA-approved drugs for cancer treatment. From the day we started this project, it took less than 20 months to initiate a clinical trial," said Julien Sage, associate professor of pediatrics and genetics at Stanford University School of Medicine in California. "This is a good example of how we can combine 'big data' and the mature field of preclinical animal models to rapidly find new uses for old drugs.

"Unlike most targeted therapies, which are often specific for a single molecule or pathway, the drugs we identified target multiple receptors at the surface of neuroendocrine cancer cells, which may make it difficult for cancer cells to develop resistance," he added. "We are in the process of identifying the optimal treatment regimen for patients with SCLC and modifying these drugs to prevent them from entering the brain, in order to minimize side effects."

SCLC is a deadly subtype of lung cancer of neuroendocrine origin, and patients diagnosed with SCLC have a dismal prognosis. There is currently no approved targeted therapy for this disease and no new drugs have been identified in the last few decades.

Sage and colleagues focused their search on drugs targeting the two top pathways identified using a bioinformatics approach: the neuroactive ligand receptor interaction pathway and the calcium signaling pathway. Of the six antidepressants initially shortlisted, imipramine and promethazine emerged as successful candidates for further study based on the results of experiments using SCLC cell lines and mice bearing human SCLC tumors.

The researchers then generated mutant mice bearing cisplatin-resistant SCLC tumors and found that the growth of chemotherapy-resistant tumors were inhibited by imipramine, suggesting that the identified antidepressants will be effective against SCLCs in patients who developed resistance to standard chemotherapy.

They conducted further experiments and found these two drugs acted on SCLCs primarily by inducing cell death mechanisms within the cancer cells. They also found that SCLC cells express certain receptors called GPCRs, and imipramine and promethazine caused cell death by engaging these receptors and their downstream signaling mechanisms.

Because imipramine was also effective in an animal model of pancreatic neuroendocrine tumors, the researchers are hoping their observations with SCLC can be extended to a number of other neuroendocrine cancers.

Based on their preclinical results, the researchers have initiated a phase 2a clinical trial to test desipramine, a drug similar to imipramine, in SCLC and other high-grade neuroendocrine tumors.

This study was funded by the Lucile Packard Foundation for Children's Health, the United States Department of Army, the NLM Biomedical Informatics Training Grant to Stanford University, the National Cancer Institute, the Stanford Dean's Fellowship, NRSA T32 Academic Research Training in Pulmonary Medicine, a California TRDRP post-doctoral fellowship, and a Stanford Cancer Institute Developmental Cancer Research Award.

The intellectual property from this work has been licensed to NuMedii, a company further developing these drugs.

[GodFather]

Takeda and L@#dbeck announce FDA approval of Brintellix™ (vortioxetine)

H. L@#dbeck A/S (L@#dbeck) and Takeda Pharmaceutical Company Limited (Takeda) jointly announced that the U.S. Food and Drug Administration (FDA) has approved Brintellix™ (vortioxetine) for the treatment of adults with major depressive disorder (MDD), a debilitating mental health illness affecting approximately 14 million adult Americans in a given year[1].

The mechanism of the antidepressant effect of Brintellix is not fully understood. It is an inhibitor of serotonin (5-HT) reuptake and that is thought to be a mechanism of its action. It is also an agonist at 5-HT1A receptors, a partial agonist at 5-HT1B receptors and an antagonist at 5-HT3, 5-HT1D and 5-HT7 receptors. The contribution of each of these activities to Brintellix's antidepressant effect has not been established. It is considered to be the first and only compound with this combination of pharmacodynamic activity. The clinical relevance of this is unknown.

"MDD is a multifaceted disorder that encompasses emotional, physical and cognitive symptoms that may make it challenging to treat," said Michael Thase, M.D., Professor of Psychiatry at the Perelman School of Medicine at the University of Pennsylvania. "Because patients respond to treatments differently, it is important to have additional new options available to help address the overall symptoms of major depression."

The efficacy and safety of Brintellix were established across a comprehensive global clinical trial program, including six positive 6-8 week short-term studies - one of which was a dedicated study in the elderly that demonstrated statistically significant improvements in overall symptoms of depression. The primary efficacy measure was the mean change from baseline to endpoint in the Hamilton Depression Scale (HAMD-24) total score in two short-term studies, including the elderly study, and the Montgomery-Asberg Depression Rating Scale (MADRS) total score in the other studies. In addition, the clinical trial program included a positive 24-64 week long-term maintenance study in which Brintellix treatment resulted in a statistically significant longer time to recurrence of depressive episodes (defined as a MADRS total score ≥ 22 or as judged by the investigator) compared to placebo. Studies evaluated for safety included more than 4,700 patients aged 18 to 88 years. It is expected that Brintellix will be available to patients by year end 2013.

"We are pleased that the FDA has approved Brintellix for the treatment of MDD, a serious and complex condition," said Charlie Baum, M.D., vice president and head, U.S. Medical and Scientific Affairs at Takeda Pharmaceuticals International. "Together with our partner L@#dbeck, we have been committed to applying our collective expertise to develop new medicines that may help people with depression."

According to The World Health Organization, fewer than half of people with depression worldwide are receiving treatment[2], and the burden of depression is expected to continue to rise globally[3]. For those who do seek treatment, discontinuation is not uncommon[4,5]. MDD is a heterogeneous disorder that does not consistently respond to therapy, thus it's important for patients to work with a healthcare provider to help find a treatment plan that works for them[6].

"There are very few new antidepressant drugs currently in development even though so many patients still struggle with depression. We are excited about the approval of Brintellix and being able to offer a new option for patients," said Anders Gersel Pedersen, executive vice president and head, Research and Development at L@#dbeck. "This approval continues our six-decade history of innovation in research and treatments for brain disorders, and underscores the commitment of the Takeda and L@#dbeck partnership to bring forward new treatments for depression."

About Brintellix™ (vortioxetine)
The mechanism of the antidepressant effect of Brintellix is not fully understood. It is an inhibitor of serotonin (5-HT) reuptake and that is thought to be a mechanism of its action. It is also an agonist at 5-HT1A receptors, a partial agonist at 5-HT1B receptors and an antagonist at 5-HT3, 5-HT1D and 5-HT7 receptors. The contribution of each of these activities to Brintellix's antidepressant effect has not been established. It is considered to be the first and only compound with this combination of pharmacodynamic activity. The clinical relevance of this is unknown.

Brintellix was discovered by L@#dbeck researchers in Copenhagen, Denmark. The clinical trial program in the U.S. was conducted jointly by L@#dbeck and Takeda, and Takeda holds the new drug application for the U.S. market. Brintellix is a trademark of H. L@#dbeck A/S and is used under license by Takeda Pharmaceuticals America, Inc.

The World Health Organization has issued a new Anatomical Therapeutic Chemical (ATC) code for Brintellix to be implemented in 2014.

The most commonly observed adverse events in MDD patients treated with Brintellix in 6-8 week placebo-controlled studies (incidence ≥5 percent and at least twice the rate of placebo) were nausea, constipation and vomiting. Overall, 5 to 8 percent of the patients who received Brintellix 5 to 20 mg/day in short-term trials discontinued treatment due to an adverse reaction, the most common being nausea, compared with 4 percent of placebo-treated patients in these studies. Brintellix and other antidepressants may cause serious side effects. See ISI below.

In clinical studies, Brintellix had no significant effect on body weight as measured by the mean change from baseline in 6-8 week placebo-controlled studies. In the 6-month, double-blind, placebo-controlled phase of a long-term study in patients who had responded to Brintellix during the initial 12-week, open-label phase, there was no significant effect on body weight between Brintellix and placebo-treated patients. Brintellix has not been associated with any clinically significant effects on vital signs, including systolic and diastolic blood pressure and heart rate, as measured in placebo-controlled studies.

The recommended starting dose of Brintellix is 10 mg once daily without regard to meals. The dose should then be increased to 20mg/day, as tolerated, because higher doses demonstrated better treatment effects in trials conducted in the U.S. The available doses provide important flexibility for physicians to help address the variability of patient needs.

The Science of Major Depression
The monoamine-deficiency theory posits that the underlying pathophysiological basis of depression is a depletion of serotonin, norepinephrine or dopamine in the central nervous system[7]. And while the exact cause of MDD is unknown, research suggests that there are multiple serotonin receptors that may be important in MDD and may influence many biologic and neurologic processesix,[8,9]. The release of bio-chemicals, such as serotonin, dopamine and norepinephrine enables impulses to be passed from one cell to another in the nervous systemix.

Takeda and L@#dbeck Alliance
In September 2007, L@#dbeck and Takeda Pharmaceutical Company Limited formed a strategic alliance for the exclusive co-development and co-commercialization in the U.S. and Japan of several compounds in L@#dbeck’s pipeline for the treatment of mood and anxiety disorders. The companies plan to co-promote Brintellix in the U.S. for the commercial launch of the product, the L@#dbeck–Takeda alliance in the U.S. will benefit from the synergy of L@#dbeck's longstanding expertise and knowledge of psychiatry and Takeda's understanding and established presence in the very important primary care environment.

About L@#dbeck
H. L@#dbeck A/S (LUN.CO, LUN DC, HLUYY) is a global pharmaceutical company specialized in brain diseases. For more than 50 years, we have been at the forefront of research within neuroscience. Our development and distribution of pioneering treatments continues to make a difference to people living with brain diseases. Our key areas of focus are alcohol dependence, Alzheimer's disease, depression/anxiety, epilepsy, Huntington's disease, Parkinson's disease, schizophrenia and stroke.

Our 5,800 employees in 57 countries are engaged in the entire value chain throughout research, development, production, marketing and sales, and are committed to improving the quality of life of people living with brain diseases. Our pipeline consists of several late-stage development programs and our products are available in more than 100 countries. We have research centers in China, Denmark and the United States, and production facilities in China, Denmark, France, Italy and Mexico. L@#dbeck generated revenue of approximately DKK15 billion in 2012 (EUR 2 billion; USD 2.6 billion).

L@#dbeck's shares are listed on the stock exchange in Copenhagen under the symbol "LUN". L@#dbeck has a sponsored Level 1 ADR program listed in the US (OTC) under the symbol "HLUYY".

About Takeda Pharmaceutical Company Limited
Located in Osaka, Japan, Takeda is a research-based global company with its main focus on pharmaceuticals. As the largest pharmaceutical company in Japan and one of the global leaders of the industry, Takeda is committed to strive towards better health for patients worldwide through leading innovation in medicine.

1. Kessler RC, BergL@#d, P., Demler, O., et al. (2003). The Epidemiology of Major Depressive Disorder Results From the National Comorbidity Survey Replication (NCS-R). Journal of the American Medical Association; 289 (23): 3196-3105.
2. Depression. Retrieved August 2 from: www.who.int/mediacentre/factsheets/fs369/en/index.html.
3. The World Health Organization (2008). The Global Burden of Disease: 2004 Update.
4. Hunot, V., Horne, R., Leese, M., Churchill, R. (2007). A Cohort Study of Adherence to Antidepressants in Primary Care: The Influence of Antidepressant Concerns and Treatment Preferences. Primary Care Companion, Journal of Clinical Psychiatry; 9(2):91-99.
5. Bull, S., et al (2002). Discontinuing or Switching Selective Serotonin-Reuptake lnhibitors. The Annals of Pharmacotherapy; 36: 578-584.
6. Gotto, J., Rapaport, M. (2005). Treatment Options in Treatment-Resistant Depression. Primary Psychiatry; 12(2):42-50.
7. Hasler, G. (2010). Pathophysiology of Depression: do we have any solid evidence of interest to clinicians? World Psychiatry, 9:155-161.
8. Nutt, DJ, (2008). Relationship of neurotransmitters to the symptoms of major depressive disorder. Journal of Clinical Psychiatry, 69 Suppl E1:4-7.
9. Filip, M., Bader, M. (2009). Overview on 5-HT receptors and their role in physiology and pathology of the central nervous system. Pharmacological Reports; 61: 761-777.

[GodFather]

Human skin wound dressings to treat cutaneous ulcers


Researchers from Université Laval's Faculty of Medicine and CHU de Québec have shown that it is possible to treat venous ulcers unresponsive to conventional treatment with wound dressings made from human skin grown in vitro. A study published recently in the journal Advances in Skin and Wound Care demonstrates how this approach was successfully used to treat venous lower-extremity ulcers in patients who had been chronically suffering from such wounds.

About 1% of the population suffers from lower-extremity ulcers. These wounds regularly become inflamed or infected and are very slow to heal, if they do at all. They are frequently associated with aging, diabetes, and circulatory system disorders such as varicose veins and oedema. "Obese individuals and those who work constantly standing up are especially vulnerable. These ulcers can persist for years. It can be a hellish clinical situation when standard treatments don't work," noted Dr. François A. Auger, director of both the study and LOEX, the tissue engineering and regenerative medicine laboratory where it was conducted.

Standard treatment for ulcers involves methodically cleaning these wounds and applying compression bandages. Drugs became available around 20 years ago but they are expensive and their efficacy has been somewhat limited. A graft using the patient's own skin can be effective but is problematic because it requires a significant amount of skin to be removed from elsewhere on the body.

This very problem inspired LOEX researchers to use their expertise with in vitro skin culture to create biomaterial-free biological wound dressing. The process is complex and requires several steps: removing 1 cm2 of skin from the patient, isolating the appropriate cells, growing them in vitro, and creating a skin substitute with both dermis and epidermis. After eight weeks of growth the self-assembled sheets of skin substitute can be applied over the ulcers, much like bandages, and replaced weekly as long as necessary. "This totally biological bandage is much more than a physical barrier," stresses Dr. Auger. "The cells secrete molecules that speed up healing by helping to set natural healing processes in motion. It would be hard to imagine a model closer to the human body's natural physiology."

Tests were successfully carried out on five patients. It took only an average of seven weeks to cure 14 ulcers that had been affecting patients for at least six months, and in some cases, several years. "This is a last recourse once all other treatment options have been exhausted," notes François A. Auger.

Dr. Auger sees another promising application for these biological bandages: "We have shown that this is effective for patients with leg ulcers. Now, we intend to carry out a clinical study to demonstrate that the same treatment works for patients with serious burns, as soon as we get the necessary approvals."

In addition to Dr. Auger, the study's co-authors are: Olivier Boa, Chanel Beaudoin Cloutier, Hervé Genest, Raymond Labbé, Bertrand Rodrigue, Jacques Soucy, Michel Roy, Frédéric Arsenault, Carlos E. Ospina, Nathalie Dubé, Marie-Hélène Rochon, Danielle Larouche, Véronique J. Moulin, and Lucie Germain.

[GodFather]

Amgen successfully completes Onyx Pharmaceuticals tender offer

Amgen (NASDAQ:AMGN) has successfully completed its previously announced tender offer to purchase all outstanding shares of common stock of Onyx Pharmaceuticals, Inc. (NASDAQ:ONXX) for $125 per share in cash. As announced on Aug. 25, the purchase price is $9.7 billion net of estimated Onyx cash. The tender offer expired at 12:00 midnight New York City time on Oct. 1, 2013. Amgen expects to complete the acquisition of Onyx later today through a merger under Section 251(h) of the General Corporation Law of the State of Delaware.

"Amgen's acquisition of Onyx fits perfectly with our commitment to advancing medicines for cancer patients around the world," said Robert A. Bradway, chairman and chief executive officer of Amgen. "We look forward to working together with the talented staff at Onyx to make the most of our exciting oncology portfolio and pipeline."

As of the expiration of the tender offer, approximately 57,698,132 shares were validly tendered and not withdrawn in the tender offer, representing approximately 78.5 percent of Onyx's outstanding shares, according to the depositary for the tender offer. The condition to the tender offer that a majority of Onyx's outstanding shares on a fully-diluted basis be validly tendered and not withdrawn has been satisfied. As a result, Amgen has accepted for payment and will promptly pay for all validly tendered shares.

As a result of the merger planned to be effected later today, all remaining eligible Onyx shares will be converted into the right to receive $125 per share in cash, without interest and less any applicable withholding taxes, the same price that was paid in the tender offer (eligible shares exclude those for which holders properly demanded appraisal under Delaware law and those held by Amgen or Onyx or their respective wholly owned subsidiaries). Following completion of the merger, Onyx shares will cease to be traded on the NASDAQ Global Market, which is expected to take effect later today.

About Amgen
Amgen is committed to unlocking the potential of biology for patients suffering from serious illnesses by discovering, developing, manufacturing and delivering innovative human therapeutics. This approach begins by using tools like advanced human genetics to unravel the complexities of disease and understand the fundamentals of human biology.

Amgen focuses on areas of high unmet medical need and leverages its biologics manufacturing expertise to strive for solutions that improve health outcomes and dramatically improve people's lives. A biotechnology pioneer since 1980, Amgen has grown to be the world's largest independent biotechnology company, has reached millions of patients around the world and is developing a pipeline of medicines with breakaway potential.

[GodFather]

Secukinumab (AIN457) showed superiority over Enbrel®

Novartis announced results from the head-to-head Phase III FIXTURE study showing secukinumab (AIN457), an interleukin-17A (IL-17A) inhibitor, was significantly superior to Enbrel®* (etanercept) in moderate-to-severe plaque psoriasis[1]. Enbrel is a current standard-of-care anti-TNF medication approved to treat moderate-to-severe plaque psoriasis. These new results were presented at the 22nd Congress of the European Association of Dermatology and Venereology (EADV) in Istanbul, Turkey[1].

The pivotal FIXTURE study met all primary and pre-specified key secondary endpoints(p<0.0001 for placebo comparisons and p=0.0250 for Enbrel comparisons)[1]. Both doses of secukinumab showed improved efficacy to Enbrel throughout the 52 week study, beginning as early as Week 2 and confirmed by Week 12 when the primary endpoints were assessed[1]. Importantly, more secukinumab patients experienced almost clear skin (described as PASI 90) and completely clear skin (PASI 100) compared to Enbrel[1], which are higher standards of skin clearance compared to the standard efficacy measures used in most psoriasis clinical studies.

"These exciting data suggest that with secukinumab, we have the potential to help more patients achieve clear skin, which is the ultimate treatment goal," said David Epstein, Head of the Pharmaceuticals Division of Novartis Pharma AG. "The data also show that specifically targeting IL-17A may offer a new and effective treatment approach for people living with moderate-to-severe plaque psoriasis."

FIXTURE compared two doses of secukinumab (300 mg and 150 mg) with Enbrel 50 mg and placebo[1]. The co-primary endpoints were assessed at Week 12 and compared secukinumab efficacy versus placebo according to the Psoriasis Area and Severity Index 75 (PASI 75) and the Investigator's Global Assessment (IGA mod 2011)[1].

The study also showed that 72% of secukinumab 300 mg patients experienced at least a 90% reduction in skin redness, thickness and scaling (PASI 90)[1] by Week 16 of the study. More than half (54%) of secukinumab 300 mg patients achieved PASI 90 as early as Week 12, compared to 21% of Enbrel patients[1]. Secukinumab 300 mg patients were also more likely to experience completely clear skin compared to those taking Enbrel in the study, as measured by PASI 100 at Week 12 (24% versus 4%)[1].

Secukinumab-treated patients also had their symptoms resolved faster than those treated with Enbrel in the study[1]. Clinically relevant differences were observed as early as Week 2, and on average secukinumab 300 mg patients had their symptoms halved by Week 3, compared to Week 8 for Enbrel patients[1].

Secukinumab efficacy was sustained over the full one year duration of the study. In FIXTURE, nearly twice as many patients treated with secukinumab 300 mg had a PASI 90 response at Week 52 compared to Enbrel (65% vs. 33%)[1].

There were no major safety signals identified in FIXTURE or the broader secukinumab Phase III clinical trial program in moderate-to-severe plaque psoriasis. In FIXTURE, the incidence of adverse events (AEs) was similar between both secukinumab treatment arms (300 mg and 150 mg), and was comparable to Enbrel[1]. The most common AEs in any treatment group (including placebo) throughout the 52 week treatment period were nasopharyngitis and headache (occurring in between 12-36 patients per 100 patient years in all groups)[1]. At the same time point, serious AEs (SAEs) were experienced by 6% of secukinumab 300 mg, 5% of secukinumab 150 mg and 6% of Enbrel patients[1]. There were no deaths reported during the study[1].

Secukinumab is the first therapy selectively targeting IL-17A to have Phase III results presented. IL-17A is a central cytokine (messenger protein) involved in the development of psoriasis, and is found in high concentrations in psoriasis skin plaques[2]-[4]. Research shows that IL-17A, in particular, plays a key role in driving the body's autoimmune response in disorders such as moderate-to-severe plaque psoriasis and is a preferred target for investigational therapies[2]-[6].

Nearly 3% of the world's population, or more than 125 million people, are affected by plaque psoriasis[7]. This is a common and debilitating disease - even those with very mild symptoms find their condition affects their everyday lives[8]. Psoriasis is also associated with psychosocial effects and those with more severe disease are at a greater risk of death from comorbid diseases such as heart disease and diabetes[9],[10].

Novartis announced top-line results from the FIXTURE study earlier this year. FIXTURE forms part of the robust secukinumab Phase III clinical trial program in moderate-to-severe plaque psoriasis that involved more than 3,300 patients in over 35 countries worldwide. Regulatory submissions of secukinumab in moderate-to-severe plaque psoriasis remain on track in the EU and US for the second half of 2013.

About FIXTURE and the secukinumab data presented at EADV
FIXTURE (the Full year Investigative eXamination of secukinumab vs. eTanercept Using 2 dosing Regimens to determine Efficacy in psoriasis) was a randomized double-blind, placebo-controlled, multicenter, global pivotal Phase III registration study involving 1,306 patients.

The co-primary endpoints were assessed at Week 12 and compared secukinumab efficacy versus placebo according to PASI 75 and IGA mod 20111. These endpoints were used also to demonstrate superiority of secukinumab vs. etanercept. Secondary measures included PASI 50, 75, 90 and 100 at different time points. In addition, the likelihood of loss of response at Week 52 was calculated by determining the proportion of patients who lost PASI 75 at Week 52, after initially achieving it at Week 12[1].

Data from an additional Phase III study of secukinumab in moderate-to-severe plaque psoriasis was also presented today at EADV[13]. The SCULPTURE (Study Comparing secukinumab Use in Long-term Psoriasis maintenance therapy: fixed regimens vs reTreatment Upon start of RElapse) trial found that patients who initially achieved PASI 75 at Week 12 were more likely to maintain their response if they received secukinumab at fixed monthly intervals, compared to treatment only on 'start of relapse'[13]. Results of two additional studies will also become available tomorrow.

About secukinumab (AIN457)
Secukinumab (AIN457) is a fully human IgG1 monoclonal antibody that selectively binds to and neutralizes IL-17A, a key pro-inflammatory cytokine[2]-[4]. Proof-of-concept and Phase II studies in moderate-to-severe plaque psoriasis and arthritic conditions (psoriatic arthritis, ankylosing spondylitis and rheumatoid arthritis) have suggested that secukinumab may potentially provide a new mechanism of action for the successful treatment of immune-mediated diseases[14]-[18]. Phase III results from two additional Phase III studies in moderate-to-severe plaque psoriasis will be presented in 2014, and in 2014 and beyond for arthritic conditions. Phase II studies are also ongoing in other areas, including multiple sclerosis.

About Novartis in specialty dermatology
Novartis is committed to developing innovative, life-changing specialty dermatology therapies redefining treatment paradigms and transforming patient care in severe skin diseases where there are remaining high unmet medical needs. The Novartis specialty dermatology portfolio includes two unique targeted products in Phase III development, secukinumab for moderate-to-severe plaque psoriasis and omalizumab (Xolair®) for chronic spontaneous urticaria (CSU). There are also more than 10 compounds in early stage development for a wide range of severe skin diseases in the Novartis specialty dermatology portfolio.

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 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 131,000 full-time-equivalent associates and operate in more than 140 countries around the world.

*Enbrel® is a registered trademark of Amgen Inc.

1. Langley R, FIXTURE oral presentation at EADV.
2. Gaffen SL. Structure and signaling in the IL-17 receptor family. Nat Rev Immunol. 2009; 9(8):556-67.
3. Ivanov S, Linden A. Interleukin-17 as a drug target in human disease. Trends Pharmacol Sci. 2009; 30(2):95-103.
4 Kopf M, Bachmann MF, Marsland BJ. Averting inflammation by targeting the cytokine environment. Nat Rev Drug Discov. 2010; 9(9):703-718.
5. Onishi RM, Gaffen SL. Interleukin-17 and its target genes: mechanisms of interleukin-17 function in disease. Immunology. 2010; 129(3):311-321.
6. Krueger J, Fretzin S, Suárez-Fariñas M, et al. IL-17A is essential for cell activation and inflammatory gene circuits in subjects with psoriasis. J Allergy Clin Immunol. 2012; 130(1):145-154.
7. International Federation of Psoriasis Associations (IFPA) World Psoriasis Day website. "About Psoriasis." www.worldpsoriasisday.com/web/page.aspx?refid=114. Accessed August 2013.
8. Mason AR, Mason J, Cork M et al. Topical treatments for chronic plaque psoriasis. Cochrane Database Syst Rev. 2009;15;(2):CD005028.
9. Abuabara K, Azfar RS, Shin DB, Neimann AL, Troxel AB, Gelfand JM. Cause-specific mortality in patients with severe psoriasis: a population-based cohort study in the U.K. Br J Dermatol. 2010 Sep;163(3):586-592
10. Gelfand JM, Troxel AB, Lewis JD, Kurd SK, Shin DB, Wang X, Margolis DJ, Strom BL. The risk of mortality in patients with psoriasis: results from a population-based study. Arch Dermatol. 2007 Dec;143(12):1493-1499.
11. Papp KA, Tyring S,Lahfa M, et al._A global phase III randomized controlled trial of etanercept in psoriasis: safety, efficacy, and effect of dose reduction. Br J Dermatol 2005;152:1304-1312.
12. Leonardi CL, Powers JL, Matheson RT, et al. Etanercept as monotherapy in patients with psoriasis. NEJM 2003;349:2014-2022.
13. SCULPTURE oral presentation at EADV.
14. Papp KA, Langley RG, Sigurgeirsson B, et al. Efficacy and safety of secukinumab in the treatment of moderate-to-severe plaque psoriasis: a randomized, double-blind, placebo-controlled phase II dose-ranging study. BJD 2013; 168, pp412-421.
15. Rich PA, Sigurgeirsson B, Thaci D, et al. Secukinumab induction and maintenance therapy in moderate-to-severe plaque psoriasis: a randomized, double-blind, placebo-controlled, phase II regimen-finding study. BJD 2013;168: 402-411.
16. Genovese MC, Durez P, Richards HB, et al. Efficacy and safety of secukinumab in patients with rheumatoid arthritis: a phase II, dose-finding, double-blind, randomised, placebo controlled study. Ann Rheum Dis 2013;72:863-869.
17. Baeten D, Sieper J, Emery P, et al. The anti-il17a monoclonal antibody secukinumab (AIN457) showed good safety and efficacy in the treatment of active ankylosing spondylitis. At: EULAR 2011, The Annual European Congress of Rheumatology, 25-28 May 2011, London, UK. Abstract 0174.
18. McInnes IB, Sieper J, Braun J, et al. Efficacy and safety of secukinumab, a fully human anti-interleukin-17A monoclonal antibody, in patients with moderate-to-severe psoriatic arthritis: a 24-week, randomised, double-blind, placebo-controlled, phase II proof-of-concept trial. Ann Rheum Dis 2013 Jan 29; doi:10.1136/annrheumdis-2012-202646.

[GodFather]

International Atherosclerosis Society and Pfizer Independent Grants for Learning & Change collaborate on new grant opportunity

The International Atherosclerosis Society (IAS) and Pfizer Independent Grants for Learning & Change (IGLC) have announced their collaboration on a new grant opportunity focused on improving care for patients around the world with medium or high levels of cardiovascular risk, with a particular focus on dyslipidemia.

The Request for Proposals (RFP) being issued by both organizations is intended to encourage organizations to submit concepts and ideas for design and implementation of scalable, sustainable programs for healthcare providers and patients in developing countries, designed to improve the management of dyslipidemia and other cardiovascular risk factors.

The IAS is an international federation of 64 national and regional societies whose basic missions are to promote the scientific understanding of the etiology, prevention, and treatment of atherosclerosis. The IAS exists to coordinate the exchange of scientific information among its member societies, to foster research into the development of atherosclerosis and related cardiometabolic diseases, and to help translate this knowledge into improving the effectiveness of programs designed to prevent and treat this disease. As such, the IAS is able to create partnerships worldwide, especially in those areas of the world where the epidemic of atherosclerosis and its related diseases is exploding and thus meet the growing needs in countries in Central and South America, in Eastern Europe, in Africa, in the Gulf Region and in South and South-East Asia.

The mission of the IGLC is to accelerate the adoption of evidence-based innovations that align the mutual interests of patients, healthcare professionals, and Pfizer, through support of independent professional education activities. The term "independent" means the initiatives funded by Pfizer are the full responsibility of the recipient organization. Pfizer has no influence over any aspect of the initiatives, and only asks for reports about the results and impact of the initiatives which it may share publicly.

Comprehensive management of lipids is increasingly recognized as an integral component of cardiovascular risk reduction. However, there remains a wide gap that separates treatment recommendations and real-world lipid management. This is especially evident in economically developing countries.

According to the World Health Organization, cardiovascular disease accounted for nearly 1 of every 3 deaths in 2004, and approximately 80% of these deaths occurred in low- and middle-income countries.[1] In 2010 the Institute of Medicine issued a report, commissioned by the National Heart, Lung, and Blood Institute, to address the increasing burden of cardiovascular disease in developing countries.[2] This report identified numerous barriers to the control of global cardiovascular disease, as well as specific recommendations to increase investment and implementation of cardiovascular disease prevention and management efforts in low- and middle-income countries. Crucial to these efforts are an increased awareness of chronic diseases as a public health priority and coordination among global, national, and regional stakeholders to strengthen healthcare systems.

This RFP is being issued today by both organizations. The IAS is the lead organization for review and evaluation of applications. A review committee, led by the IAS, will ultimately make decisions on which proposals will receive funding. Grant funding will be provided by Pfizer. Collectively, up to $2 million is available for award. Initially, project concepts and ideas must be submitted as "Letters of Intent" to the Pfizer website by the deadline of October 31, 2013 and must be a maximum of 3-pages in length.

Only the member societies of the IAS or their partner organizations may submit Letters of Intent to this RFP. Partnering and collaboration is strongly encouraged.

Organizations interested in responding to this RFP should reach out to the IAS member society in their country or region of the world and submit a collaborative proposal. Similarly, IAS member societies interested in responding to this RFP should bring into their project appropriate partner organizations such as academic medical centers, hospitals or healthcare systems, and other societies or associations.

For further information about the RFP please email [e-mail] or [e-mail] or visit the organization websites below.

For the IAS, please visit the website: athero.org

For Pfizer IGLC, please visit the website: www.pfizer.com/responsibility/grants_contributions/independent_grants

Pfizer Inc.: Working together for a healthier world™
At Pfizer, we apply science and our global resources to bring therapies to people that extend and significantly improve their lives. We strive to set the standard for quality, safety and value in the discovery, development and manufacture of health care products. Our global portfolio includes medicines and vaccines as well as many of the world's best-known consumer health care products. Every day, Pfizer colleagues work across developed and emerging markets to advance wellness, prevention, treatments and cures that challenge the most feared diseases of our time. Consistent with our responsibility as one of the world's premier innovative biopharmaceutical companies, we collaborate with health care providers, governments and local communities to support and expand access to reliable, affordable health care around the world. For more than 150 years, Pfizer has worked to make a difference for all who rely on us.

1. World Health Organization (WHO). Cardiovascular Diseases (CVDs). Fact Sheet No. 317. Geneva, Switzerland: WHO; 2011. www.who.int/mediacentre/factsheets/fs317/en/print.html. Accessed May 16, 2012.
2. Institute of Medicine (IOM). Fuster V, Kelly BB eds. Promoting Cardiovascular Health in the Developing World: A Critical Challenge to Achieve Global Health. Washington, DC: National Academies Press; 2010. www.nap.edu/catalog.php?record_id=12815. Accessed May 16, 2012.

[GodFather]

Massive DNA study points to new heart drug targets and a key role for triglycerides

A global hunt for genes that influence heart disease risk has uncovered 157 changes in human DNA that alter the levels of cholesterol and other blood fats - a discovery that could lead to new medications. Each of the changes points to genes that can modify levels of cholesterol and other blood fats and are potential drug targets. Many of the changes point to genes not previously linked to blood fats, also called lipids. A surprising number of the variations were also associated with coronary artery disease, type 2 diabetes, obesity, and high blood pressure.

The research also reveals that triglycerides - another type of blood lipid - play a larger role in heart disease risk than previously thought.

The results, published in two new papers appearing simultaneously in the journal Nature Genetics, come from the Global Lipids Genetics Consortium (GLGC) - a worldwide team of scientists who pooled genetic and clinical information from more than 188,000 people from many countries and heritages.

The analysis of the combined data was led by a team from the University of Michigan Medical School and School of Public Health. They used sophisticated computing and statistical techniques to search for genetic variations that modify blood lipid levels.

The results increase by more than a third the total number of genetic variants linked to blood lipids. All but one of the variants associated with blood lipids are near stretches of DNA that encode proteins.

"These results give us 62 new clues about lipid biology, and more places to look than we had before," says Cristen Willer, Ph.D., the lead author of one paper and an assistant professor of Internal Medicine, Human Genetics and Computational Medicine & Bioinformatics at the U-M Medical School. "Once we take the time to truly understand these clues, we'll have a better understanding of lipid biology and cardiovascular disease - and potentially new targets for treatment."

But, cautions senior author and U-M School of Public Health Professor Gonçalo Abecasis, Ph.D., it will take much further work to study the implicated genes and to find and test potential drugs that could target them. The consortium's "open science" approach will include publishing further detail online for other researchers to use freely toward this goal.

A further analysis of the massive dataset, published as a letter with lead authors Sekar Kathiresan and Ron Do from Harvard University and the Broad Institute, suggests that triglyceride levels have more impact on cardiovascular disease risk than previously thought.

This analysis found that genetic variations that increase triglyceride or LDL-cholesterol levels are also associated with higher incidence of heart disease. But the analysis also casts further doubt on the role of high density lipoprotein, known commonly as HDL or "good cholesterol", in heart disease risk. In recent years, many drugs that modify HDL cholesterol have failed to show a benefit in preventing heart disease.

"We couldn't have done this on our own. Great scientists are usually very competitive, but it is great when we come together and accelerate progress." says Abecasis, who is the Felix E. Moore Collegiate Professor of Biostatistics, and director of the U-M Computational and Translational Genomics Initiative.

The GLGC is focused on finding, cataloging and analyzing genetic variations that modify blood lipids and heart disease risk. The researchers had access to a new tool - a custom DNA analysis chip they helped design that allows inexpensive analysis of DNA in studies of cardiovascular and metabolic traits.

Combined with genome-wide association study (GWAS) techniques, and the sheer number and diversity of the participants engaged by the researchers, the chip helped make the research possible on a much larger scale than ever before.

U-M graduate students Ellen M. Schmidt and Sebanti Sengupta - studying Bioinformatics and Biostatistics, respectively - played key roles in analysis of data, blending their skills to handle a massive amount of data and feed it through powerful computers.

Willer says the new knowledge published in the papers should fuel drug development and experiments in animal models of cardiovascular risk. But in her specialty, probing huge amounts of genetic data, the next steps include looking for "networks" of genes that interact with one another, to try to glean clues about the function of the lesser-understood genes.

Looking for rare genetic variants that are linked with the most severe forms of lipid disorder and heart disease is another challenge, she says. The overlap between these rare, serious variations, and the more common but less severe variations, could help understanding of basic lipid biology.

In addition to the U-M authors mentioned above, the research team included U-M biostatistics professor Michael Boehnke, Ph.D., and dozens of scientists and students from around the world. A full list of authors and affiliations is on each of the papers.

Dr. Willer holds a Pathway to Independence Award (K99/R00) from the National Heart, Lung, and Blood Institute. Ellen Schmidt holds a National Science Foundation Open Data fellowship. Other funding came from the funders of each of the genetic cohort studies that contributed data to the GLGC.

Nature Genetics, doi:10.1038/ng.2797 and doi:10.1038/ng.2795

[GodFather]

Stem cells engineered to become targeted drug factories


A group of Brigham and Women's Hospital, and Harvard Stem Cell Institute researchers, and collaborators at MIT and Massachusetts General Hospital have found a way to use stem cells as drug delivery vehicles. The researchers inserted modified strands of messenger RNA into connective tissue stem cells - called mesenchymal stem cells - which stimulated the cells to produce adhesive surface proteins and secrete interleukin-10, an anti-inflammatory molecule. When injected into the bloodstream of a mouse, these modified human stem cells were able to target and stick to sites of inflammation and release biological agents that successfully reduced the swelling.

"If you think of a cell as a drug factory, what we're doing is targeting cell-based, drug factories to damaged or diseased tissues, where the cells can produce drugs at high enough levels to have a therapeutic effect," said research leader Jeffrey Karp, PhD, a Harvard Stem Cell Institute principal faculty member and Associate Professor at the Brigham and Women's Hospital, Harvard Medical School, and Affiliate faculty at MIT.

Karp's proof of concept study, published in the journal Blood, is drawing early interest from biopharmaceutical companies for its potential to target biological drugs to disease sites. While ranked as the top sellers in the drug industry, biological drugs are still challenging to use, and Karp's approach may improve their clinical application as well as improve the historically mixed, clinical trial results of mesenchymal stem cell-based treatments.

Mesenchymal stem cells have become cell therapy researchers’ tool of choice because they can evade the immune system, and thus are safe to use even if they are derived from another person. To modify the cells with messenger RNA, the researchers used the RNA delivery and cell programming technique that was previously developed in the MIT laboratory of Mehmet Fatih Yanik, PhD. This RNA technique to program cells is harmless, as it does not modify the cells' genome, which can be a problem when DNA is used (via viruses) to manipulate gene expression.

"This opens the door to thinking of messenger RNA transfection of cell populations as next generation therapeutics in the clinic, as they get around some of the delivery challenges that have been encountered with biological agents," said Oren Levy, PhD, co-lead author of the study and Instructor of Medicine in Karp's lab. The study was also co-led by Weian Zhao, PhD, at University of California, Irvine who was previously a postdoctoral fellow in Karp's lab.

One such challenge with using mesenchymal stem cells is they have a "hit-and-run" effect, since they are rapidly cleared after entering the bloodstream, typically within a few hours or days. The Harvard/MIT team demonstrated that rapid targeting of the cells to the inflamed tissue produced a therapeutic effect despite the cells being rapidly cleared. The scientists want to extend cell lifespan even further and are experimenting with how to use messenger RNA to make the stem cells produce pro-survival factors.

"We're interested to explore the platform nature of this approach and see what potential limitations it may have or how far we can actually push it," Zhao said. "Potentially, we can simultaneously deliver proteins that have synergistic therapeutic impacts."

The research was a highly collaborative effort. In addition to Karp, Levy, and Zhao, collaborators included co-corresponding author Yanik, and Harvard Stem Cell Institute Affiliated Faculty member Charles Lin, PhD, at Massachusetts General Hospital.

The work was supported by the National Institutes of Health, the American Heart Association, and a Prostate Cancer Foundation Challenge Award.

[GodFather]

Better outcome in case of major bleed for patients taking the anticoagulant Pradaxa® compared to warfarin

Anticoagulants are an indispensable treatment to prevent dangerous blood clots that can cause devastating ischaemic strokes in patients with atrial fibrillation or life-threatening pulmonary embolism in patients with venous thromboembolism.(1,2) An increased risk of bleeding is a known possible complication of all anticoagulant therapies.(3) This research shows that applying existing management strategies in case of a major bleed with Pradaxa® compared to a major bleed with warfarin resulted in better outcomes even without the availability of a specific antidote.(4)

A post-hoc analysis of five Phase III trials compared the management and outcomes of a major bleeding event in patients taking Pradaxa® (dabigatran etexilate) with major bleeding events in patients taking warfarin. The results are now published online in Circulation. The analysis showed that the 30-day mortality (death within one month) related to a major bleeding event was significantly lower with Pradaxa® than with warfarin in atrial fibrillation patients requiring long-term treatment in the RE-LY® trial. In addition, Pradaxa® treated patients could leave the Intensive Care Unit faster than warfarin treated patients.

When major bleeding did occur in the trials analysed, the patients were managed using standard strategies and treatment options currently available in the clinical setting, both for Pradaxa® and warfarin.(4) This better outcome in case of a major bleed, even in the absence of a specific antidote, provides crucial support for the positive benefit-risk profile of Pradaxa®.

"We found that atrial fibrillation patients, who had a major bleed during therapy, actually had better outcomes if they took dabigatran than if they took warfarin," said Prof. Sam Schulman, Division of Hematology and Thromboembolism, McMaster University, Hamilton, Canada. "It is reassuring to see that existing standard strategies, such as stopping the drug and replacing blood, work just as well with dabigatran treatment as they do with warfarin treatment – if not even better."

The analysis also found that patients who had a major bleeding event during Pradaxa® treatment were usually at higher baseline risk compared to patients with major bleeding events on warfarin - Pradaxa® patients were older, had worse renal function and more often used concomitant treatment with aspirin or non-steroid anti-inflammatory agents.(4)

The pooled post-hoc analysis featured data from five large long-term Phase III trials including the pivotal RE-LY® trial comparing Pradaxa® with warfarin for stroke prevention in non-valvular atrial fibrillation and trials in acute treatment / secondary prevention of venous thromboembolism (VTE). The trials had durations of six to 36 months and included 27,419 patients. Key results are:(4)

Lower 30-day mortality in case of a first major bleed in the combined Pradaxa® treatment group compared to the warfarin group in atrial fibrillation patients (odds ratio 0.56, p=0.009)
When outcomes for all indications were combined and adjusted, the data showed a strong trend to lower mortality for Pradaxa® compared to warfarin (odds ratio 0.66, p=0.051)
One day shorter stay in the intensive care unit required for Pradaxa® patients (mean 1.6 nights) compared with warfarin patients (mean 2.7 nights; p=0.01)
Most major bleeds were managed mainly with supportive care using standard clinical measures. The most common measures used were blood transfusions and plasma transfusions.

"These findings provide important and reassuring insights for both physicians and patients", commented Professor Klaus Dugi, Corporate Senior Vice President Medicine, Boehringer Ingelheim. "They demonstrate that even in the absence of a specific antidote, when existing standard strategies are used, patients can expect a better outcome with Pradaxa® than with warfarin should a major bleed occur."

The favourable benefit-risk profile of Pradaxa® is supported by safety assessments from regulatory authorities including the European Medicines Agency and the U.S. Food and Drug Administration (FDA).(5,6) The most recent FDA update reports the results of a Mini-Sentinel assessment that indicated bleeding rates associated with new use of Pradaxa® are not higher than those associated with new use of warfarin. Specifically, for intracranial haemorrhage and gastrointestinal haemorrhage, the combined incidence rate (per 100,000 days at risk) was 1.8 to 2.6 times higher for new users of warfarin than for new users of Pradaxa®.(6)

Pradaxa® is already widely approved for stroke prevention in atrial fibrillation and for primary prevention of VTE following total hip replacement or total knee replacement surgery.7 The extensive in-market experience of over 2 million patient-years in all licensed indications puts Pradaxa® first among the novel oral anticoagulants.(8)

About Pradaxa® (dabigatran etexilate)
Pradaxa® is approved in over 100 countries worldwide.(8) 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.(7)

Pradaxa®, a direct thrombin inhibitor (DTI),(9) 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 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. Marini C, et al. From a Population-Based Study Contribution of Atrial Fibrillation to Incidence and Outcome of Ischemic Stroke: Results From a Population-Based Study. Stroke. 2005;36:1115-9.
2. 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 Syst Rev. 2005;(3):CD001927.
3. Levine MN, et al. Hemorrhagic complications of anticoagulant treatment. Chest. 2001;119(1,Suppl.):108S–21S.
4. Majeed A, et al. Management and outcomes of major bleeding during treatment with dabigatran or warfarin. Circulation. 2013; published online before print September 30 2013, doi:10.1161/CIRCULATIONAHA.113.00233
5. European Medicines Agency Press release - 25 May 2012: EMA/337406/2012. European Medicines Agency updates patient and prescriber information for Pradaxa. www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2012/05/news_detail_001518.jsp&mid=WC0b01ac058004d5c1 Last accessed 7 October 2013.
6. FDA Drug Safety Communication: Update on the risk for serious bleeding events with the anticoagulant Pradaxa (dabigatran) - 2 November 2012 www.fda.gov/Drugs/drugsafety/ucm326580.htm Last accessed 7 October2013.
7. Pradaxa® European Summary of Product Characteristics, 2013
8. Boehringer Ingelheim data on file.
9. Di Nisio M, et al. Direct thrombin inhibitors. N Engl J Med. 2005;353:1028-40.

[GodFather]

The Nobel Prize in Physiology or Medicine 2013

The Nobel Assembly at Karolinska Institutet has today decided to award The 2013 Nobel Prize in Physiology or Medicine jointly to James E. Rothman, Randy W. Schekman and Thomas C. Südhof for their discoveries of machinery regulating vesicle traffic, a major transport system in our cells. The 2013 Nobel Prize honours three scientists who have solved the mystery of how the cell organizes its transport system. Each cell is a factory that produces and exports molecules. For instance, insulin is manufactured and released into the blood and chemical signals called neurotransmitters are sent from one nerve cell to another. These molecules are transported around the cell in small packages called vesicles. The three Nobel Laureates have discovered the molecular principles that govern how this cargo is delivered to the right place at the right time in the cell.

Randy Schekman discovered a set of genes that were required for vesicle traffic. James Rothman unravelled protein machinery that allows vesicles to fuse with their targets to permit transfer of cargo. Thomas Südhof revealed how signals instruct vesicles to release their cargo with precision.

Through their discoveries, Rothman, Schekman and Südhof have revealed the exquisitely precise control system for the transport and delivery of cellular cargo. Disturbances in this system have deleterious effects and contribute to conditions such as neurological diseases, diabetes, and immunological disorders.

How cargo is transported in the cell
In a large and busy port, systems are required to ensure that the correct cargo is shipped to the correct destination at the right time. The cell, with its different compartments called organelles, faces a similar problem: cells produce molecules such as hormones, neurotransmitters, cytokines and enzymes that have to be delivered to other places inside the cell, or exported out of the cell, at exactly the right moment. Timing and location are everything. Miniature bubble-like vesicles, surrounded by membranes, shuttle the cargo between organelles or fuse with the outer membrane of the cell and release their cargo to the outside. This is of major importance, as it triggers nerve activation in the case of transmitter substances, or controls metabolism in the case of hormones. How do these vesicles know where and when to deliver their cargo?

Traffic congestion reveals genetic controllers
Randy Schekman was fascinated by how the cell organizes its transport system and in the 1970s decided to study its genetic basis by using yeast as a model system. In a genetic screen, he identified yeast cells with defective transport machinery, giving rise to a situation resembling a poorly planned public transport system. Vesicles piled up in certain parts of the cell. He found that the cause of this congestion was genetic and went on to identify the mutated genes. Schekman identified three classes of genes that control different facets of the cell´s transport system, thereby providing new insights into the tightly regulated machinery that mediates vesicle transport in the cell.

Docking with precision
James Rothman was also intrigued by the nature of the cell´s transport system. When studying vesicle transport in mammalian cells in the 1980s and 1990s, Rothman discovered that a protein complex enables vesicles to dock and fuse with their target membranes. In the fusion process, proteins on the vesicles and target membranes bind to each other like the two sides of a zipper. The fact that there are many such proteins and that they bind only in specific combinations ensures that cargo is delivered to a precise location. The same principle operates inside the cell and when a vesicle binds to the cell´s outer membrane to release its contents.

It turned out that some of the genes Schekman had discovered in yeast coded for proteins corresponding to those Rothman identified in mammals, revealing an ancient evolutionary origin of the transport system. Collectively, they mapped critical components of the cell´s transport machinery.

Timing is everything
Thomas Südhof was interested in how nerve cells communicate with one another in the brain. The signalling molecules, neurotransmitters, are released from vesicles that fuse with the outer membrane of nerve cells by using the machinery discovered by Rothman and Schekman. But these vesicles are only allowed to release their contents when the nerve cell signals to its neighbours. How is this release controlled in such a precise manner? Calcium ions were known to be involved in this process and in the 1990s, Südhof searched for calcium sensitive proteins in nerve cells. He identified molecular machinery that responds to an influx of calcium ions and directs neighbour proteins rapidly to bind vesicles to the outer membrane of the nerve cell. The zipper opens up and signal substances are released. Südhof´s discovery explained how temporal precision is achieved and how vesicles´ contents can be released on command.

Vesicle transport gives insight into disease processes
The three Nobel Laureates have discovered a fundamental process in cell physiology. These discoveries have had a major impact on our understanding of how cargo is delivered with timing and precision within and outside the cell. Vesicle transport and fusion operate, with the same general principles, in organisms as different as yeast and man. The system is critical for a variety of physiological processes in which vesicle fusion must be controlled, ranging from signalling in the brain to release of hormones and immune cytokines. Defective vesicle transport occurs in a variety of diseases including a number of neurological and immunological disorders, as well as in diabetes. Without this wonderfully precise organization, the cell would lapse into chaos.

James E. Rothman was born 1950 in Haverhill, Massachusetts, USA. He received his PhD from Harvard Medical School in 1976, was a postdoctoral fellow at Massachusetts Institute of Technology, and moved in 1978 to Stanford University in California, where he started his research on the vesicles of the cell. Rothman has also worked at Princeton University, Memorial Sloan-Kettering Cancer Institute and Columbia University. In 2008, he joined the faculty of Yale University in New Haven, Connecticut, USA, where he is currently Professor and Chairman in the Department of Cell Biology.

Randy W. Schekman was born 1948 in St Paul, Minnesota, USA, studied at the University of California in Los Angeles and at Stanford University, where he obtained his PhD in 1974 under the supervision of Arthur Kornberg (Nobel Prize 1959) and in the same department that Rothman joined a few years later. In 1976, Schekman joined the faculty of the University of California at Berkeley, where he is currently Professor in the Department of Molecular and Cell biology. Schekman is also an investigator of Howard Hughes Medical Institute.

Thomas C. Südhof was born in 1955 in Göttingen, Germany. He studied at the Georg-August-Universität in Göttingen, where he received an MD in 1982 and a Doctorate in neurochemistry the same year. In 1983, he moved to the University of Texas Southwestern Medical Center in Dallas, Texas, USA, as a postdoctoral fellow with Michael Brown and Joseph Goldstein (who shared the 1985 Nobel Prize in Physiology or Medicine). Südhof became an investigator of Howard Hughes Medical Institute in 1991 and was appointed Professor of Molecular and Cellular Physiology at Stanford University in 2008.

Key publications:

Novick P, Schekman R: Secretion and cell-surface growth are blocked in a temperature-sensitive mutant of Saccharomyces cerevisiae. Proc Natl Acad Sci USA 1979; 76:1858-1862.
Balch WE, Dunphy WG, Braell WA, Rothman JE: Reconstitution of the transport of protein between successive compartments of the Golgi measured by the coupled incorporation of N-acetylglucosamine. Cell 1984; 39:405-416.
Kaiser CA, Schekman R: Distinct sets of SEC genes govern transport vesicle formation and fusion early in the secretory pathway. Cell 1990; 61:723-733.
Perin MS, Fried VA, Mignery GA, Jahn R, Südhof TC: Phospholipid binding by a synaptic vesicle protein homologous to the regulatory region of protein kinase C. Nature 1990; 345:260-263.
Sollner T, Whiteheart W, Brunner M, Erdjument-Bromage H, Geromanos S, Tempst P, Rothman JE: SNAP receptor implicated in vesicle targeting and fusion. Nature 1993; 362:318-324.
Hata Y, Slaughter CA, Südhof TC: Synaptic vesicle fusion complex contains unc-18 homologue bound to syntaxin. Nature 1993; 366:347-351.