Gene Linked to Fatal Inflammatory Disease in Children


Autoinflammatory diseases are a class of conditions in which the immune system, seemingly unprovoked, becomes activated and triggers inflammation. Normally, the inflammatory response helps quell infections, but the prolonged inflammation that occurs in these diseases can damage the body.


According to an article published online in the New England Journal of Medicine (16 July 2014), investigators at the NIH have identified a gene that underlies a very rare but devastating autoinflammatory condition in children. Fortunately, several existing drugs have shown therapeutic potential in laboratory studies, and one is currently being studied in children with the disease, which is named STING-associated vasculopathy with onset in infancy (SAVI). The senior author of the study, Raphaela Goldbach-Mansky, M.D., and the co-lead authors, Yin Liu, M.D., Ph.D., Adriana A. Jesus, M.D., Ph.D., and Bernadette Marrero, Ph.D., are in the NIAMS Translational Autoinflammatory Disease Section.


In 2004, a 10-year-old girl with signs of systemic inflammation, especially in the blood vessels, who had not responded to any medications, presented at NIH. She had blistering rashes on her fingers, toes, ears, nose and cheeks, and had lost parts of her fingers to the disease. The child also had severe scarring in her lungs and was having trouble breathing. She had shown signs of the disease as an infant and had progressively worsened. Tragically, she died a few years later.


By 2010, two other patients were seen with the same symptoms. The research team suspected that all three had the same disease, and that it was caused by a genetic defect that arose in the children themselves, rather than having been inherited from their parents, who were not affected. As a result, DNA comparison revealed a novel mutation in a gene that encodes a protein called STING, a known signaling molecule whose activation leads to production of interferon, a key immune regulator. When overproduced, however, interferon can trigger inflammation. Blood tests on the affected children had shown high levels of interferon-induced proteins, so it was not surprising when the mutated gene turned out to be related to interferon signaling. Then, when the DNA of five other patients with similar symptoms was tested, mutations in the same gene were found, confirming STING’s role in the disease.


It was, therefore, concluded that the mutations in STING boosted the protein’s activity resulting in excessive inflammation along with other evidence of interferon pathway activation. Interferon normally works to restrict an invading pathogen’s ability to replicate by triggering a function that stimulates immune cells. But prolonged activation of the pathway leads to chronic inflammation and damage to tissues and organs. The researchers also found that STING was present in high levels in the cells lining the blood vessels and the lungs, which would likely explain why these tissues are predominantly affected by the disease.


The research team next looked for ways to mitigate the inflammatory response in patients with SAVI. Several drugs in the janus kinase (JAK) inhibitor class: tofacitinib (Pfizer), ruxolitinib (Incyte and Novartis) and baricitinib (Incyte and Lilly), are known to work by blocking the interferon pathway. As a result, when the effect of the drugs were tested on SAVI patients’ blood cells in the lab, a marked reduction in interferon-pathway activation was observed.


SAVI patients are now being enrolled in an expanded access program, also known as a compassionate use protocol. Compassionate use protocols allow doctors to give investigational medicines to patients with serious diseases or conditions for which there is no comparable or satisfactory alternative therapy to treat the patient’s disease or condition.

New Treatment Increases Pregnancy Rate in Women With PCOS


Polycystic ovary syndrome (PCOS) affects from 5 to 10% of reproductive age women and may be the most common cause of female infertility. With PCOS, the ovaries are enlarged and contain multiple small cyst-like structures (immature ovarian follicles). Women with PCOS may produce an excess of male hormones, which interferes with ovulation. In addition to infertility, PCOS symptoms include irregular menstrual periods, excessive body and facial hair, acne, and obesity. Women with PCOS also may experience insulin resistance, a prediabetic condition in which higher-than-normal amounts of insulin are produced to maintain normal blood glucose levels.


Letrozole, currently used as a treatment for breast cancer in women who have gone through menopause, inhibits the production of estrogen, which influences the action of the brain’s hypothalamus and pituitary on the functioning of the ovaries. Clomiphene prevents estrogen from binding to its target on the cell and so acts on the pituitary to cause the ovary to release the egg cell.


According to an article published in the new England Jornal of Medicine (2014;371:119-129), letrozole appears to be more effective than the standard drug clomiphene for helping women with PCOS to achieve pregnancy. The study found that that women treated with letrozole not only were more likely to ovulate than were women treated with the standard drug, clomiphene, but were also more likely to have a live birth.


The study enrolled 750 infertile women with PCOS who were between 18 and 40 years of age, from February 2009 through January 2012. The women were assigned at random to receive either clomiphene or letrozole for 5 days, beginning on the third day of their menstrual cycle, for up to 5 monthly cycles. If a woman failed to ovulate or if their test results indicated that they produced insufficient progesterone following ovulation, the dose of the drug was increased during the next monthly cycle. Women with test results indicating conception had occurred were followed until an ultrasound exam could confirm that a pregnancy had been established and throughout pregnancy until delivery.


Results showed that of the 374 women who received letrozole, 103 (27.5%) eventually had a live birth, and of the 376 women who received clomiphene, 72 (19.1%) experienced a live birth. The cumulative ovulation rate was also higher for the letrozole group, with ovulation occurring 834 times in 1352 cycles, or 61.7% of the time. The women in the clomiphene group ovulated 688 times out of a total of 1425 cycles, or 48.3% of the time.


There were no statistically significant differences between the groups for:


1. Multiple pregnancy, with twin pregnancies occurring in 3.4% among the letrozole group and 7.4% of the clomiphene group

2. Pregnancy loss (31.8% of the letrozole group and 29.1% of the clomiphene group

3. Infants born with birth defects (3.9% with letrozole and 1.4% with clomiphene)


In terms of adverse events, women treated with letrozole had significantly fewer hot flashes than those treated with clomiphene, but more dizziness and fatigue.


The study authors noted that one prior study suggested that letrozole might increase the risk of birth defects, but added that their study results do not support the earlier study’s findings. Although the study did not uncover an increased risk of birth defects, the authors concluded that additional studies are needed to rule out whether letrozole could pose a similar or greater risk of birth defects than do other infertility treatments.


TARGET HEALTH excels in Regulatory Affairs. Each week we highlight new information in this challenging area.


FDA Approves Drug to Treat Acute Hereditary Angioedema (HAE)


Target Health began working in 2003 with Dr. Bernd Rosenkranz and Jerini AG (acquired by Shire, now Abbvie) for the first product approved by FDA for Hereditary angioedema (HAE). We worked with Bernd on obtaining orphan drug designation and the original IND, and Target e*CRF was used for the first clinical trial. FDA Approved FIRAZYR® (icatibant injection) for acute attacks of HAE in 2011.


HAE, which is caused by having insufficient amounts of a plasma protein called C1-esterase inhibitor, affects approximately 6,000 to 10,000 people in the United States. People with HAE can develop rapid swelling of the hands, feet, limbs, face, intestinal tract, or airway. These acute attacks of swelling can occur spontaneously, or can be triggered by stress, surgery or infection. Swelling of the airway is potentially fatal without immediate treatment.


The FDA has approved Ruconest, the first recombinant C1-Esterase Inhibitor product for the treatment of acute attacks in adult and adolescent patients with HAE. Ruconest is a human recombinant C1-esterase inhibitor purified from the milk of genetically modified (transgenic) rabbits. Ruconest is intended to restore the level of functional C1-esterase inhibitor in a patient’s plasma, thereby treating the acute attack of swelling.


The safety and efficacy of Ruconest was evaluated in a multicenter controlled clinical trial. Forty-four adult and adolescent patients with acute attacks were treated with Ruconest. The most common adverse reactions reported in patients treated with Ruconest were headache, nausea and diarrhea.


Ruconest received orphan-drug designation for acute attacks by the FDA because it is intended for treatment of a rare disease or condition.


Ruconest is manufactured by Pharming Group NV, Leiden, the Netherlands, and will be distributed in the United States by Santarus Inc., a wholly owned subsidiary of Salix Pharmaceuticals Inc., Raleigh, North Carolina.

Almond Pear Cake


For the pears


1 pound pears, rinsed and dried

1 lemon

3/4 cup granulated Splenda


For the almond cake


Canola spray for 9 inch spring-form pan

7 ounces almond paste

1/4 cup granulated Splenda

4 ounces unsalted butter, cut into small pieces and chilled

2 Tablespoons honey

3 large eggs

4 Tablespoons Amaretto, plus a lot extra to pour over cake

1/3 cup almond flour, sifted

Kosher salt

1/2 cup additional Amaretto, to go with the fruit

1 cup sliced almonds, toasted at home (garnish)

Confectioners’ Splenda

Cool whip (garnish), Creme fraiche, whipped to soft peaks




Make the pears


1. Select about 3 slices of the pears, after cut in half. Then cut the half in lengthwise slices, and set aside.

2. Cut the remaining pears in halves or quarters so that the pieces are about the same size. (You should have about 1 1/2 cups.) Place them in a medium saucepan.

3. Use a fine grater to zest the lemon. Add 1 teaspoon of the zest to the pan. Squeeze 1 Tablespoon of juice and add it to the pan. Add the Splenda and stir to coat the fruit.

4. Add Amaretto to the pears and stir.

5. Place the pan over medium-high heat and cook, stirring often to dissolve the sugar. By the time the sugar has dissolved, the fruit will have released a lot of juice. Boil for about 4 minutes to reduce the liquid somewhat, then reduce the heat and simmer for another 2 minutes. Don’t worry if some of the pear is soft and falls apart.

6. Take pan off the stove and stir in reserved pears. Cool to room temperature. Serve either on top of the cake, or next to each individual serving of cake. Garnish top of cake with the first 3 slices (see photo)

Refrigerate left-over fruit in a covered container.




Bottom of cake after baking. Now, turn it over. But if you don’t want to, it doesn’t matter. ©Joyce Hays, Target Health Inc.


Make the cake


1. Spray sides of an 8 or 9-inch spring-form cake pan. Line bottom of pan with a circle of parchment paper.

2. Place the almond paste and Splenda in the bowl of a heavy-duty mixer fitted with the paddle attachment, or in another large bowl if using a handheld mixer. Begin to cream the mixture on low speed to break up the almond paste, then increase the speed to medium for about 2 minutes, or until the paste is broken into fine particles.

3. Add the butter and mix for 4 to 5 minutes, or until the mixture is light in color and airy; stop the machine and scrape down the sides as necessary. It is important to mix long enough or the cake will have a dense texture.

4. Mix in the honey, then add the eggs one at a time, beating until each one is fully incorporated before adding the next. Add the amaretto, flour, and a pinch of salt and mix just to combine.

5. Scrape the batter into the prepared pan and smooth the top. Bake for about 25 minutes, or until the cake is golden and springs back when pressed. Watch the cake constantly so it doesn’t burn. Transfer to a rack to cool.

6. Invert the large cake onto the rack, remove the parchment paper, and invert the cake again so that the top is once again facing upward. Brush the top of the cake(s) with Amaretto, or pour Amaretto into a measuring cup for easy pouring and slowly add 1/2 cup or more, to top of cake. It will sit on top for a while so let it get absorbed. Don’t be shy adding the Amaretto. Next, add the three sliced pears to top of cake. Now, sprinkle the toasted almonds, all over top of cake. Dust with Splenda confectioners’ sugar (optional). Serve with a dollop of cool whip or whipped creme fraiche and the cooked/cooled pears (optional).



Going                                                                                                Going



Nearly gone (one sitting, two people) ©Joyce Hays, Target Health Inc.


Pictures are worth many words – can you tell how delicious this cake is/was?


We ate light, a vegetarian dinner, of veggie burgers topped with chopped tomatoes, avocados and cooked shallots, some farfalle and the New Zealand sauvignon blanc we discovered in a previous newsletter. Our attention then turned to the new recipe – dessert. Out the window went our health concerns. Although, we don’t read Time Magazine for serious news, we did notice one of their recent cover photos, a close-up of butter, and, announcing that doctors were now giving their “okay“ to eat it again.  We don’t agree with these doctors or with Time Magazine, which is why we mention it here. But for a brief dessert time, usually allotted for fresh fruit, we sampled the new cake.  It was unbelievably delicious! Jules simply devoured it!


Let me come to the rescue. Let’s say you liked the photos of this Almond Pear Cake, but have the will power to, just say no. I’ve already thought about that. Take a look below, for the alternative:




No butter alternative, pear almond cake with hundreds of fewer calories ©Joyce Hays, Target Health Inc.


This is 99.9% the same recipe. The only change is that I substituted the butter for 1/2 of a container of tofutti (soy cream cheese). I tried a slightly different garnish. After slowly pouring a great deal of Amaretto on top, waiting patiently for it to soak (by poking a fork all across the top, the soaking process was speeded up), I used some of the cooked pear mixture to cover the top (instead of sliced pears), then sprinkled the toasted almonds all over everything.


Here’s the thing. If you never tasted the cake with butter, you will love this version of the recipe. It’s delicious but dryer (so needs more Amaretto). It’s less rich, but you won’t know that if you didn’t make the butter version.


Which ever version you decide to make, this is the perfect anytime cake. Wonderful with coffee so serve for brunch, lunch dessert and of course an evening dessert. You will find your family members snacking on it, as well.




From Our Table to Yours!


Bon Appetit !

Society for Clinical Research Sites


Target Health is pleased that The Society for Clinical Research Sites (SCRS) has highlighted Target Health’s approach to eSource and the paperless clinical trial in their Newsletter, InFocus. As a Site Development Partner, Target Health works closely with key SCRS stakeholders, including its Global Impact Partners and members of the Society’s Leadership Council, to set key initiatives that will elevate site performance and enhance site sustainability.


eSource Conference in Clinical Investigations


Target Health is pleased that Dean Gittleman, Sr. Director of Operations, will be presenting on the topic: “Achieve eSource Data Compliance by Eliminating the Need for Paper“ at the Ensure Regulatory Compliance and Data Integrity Through Effective Electronic Source Data Implementation conference being held in Philadelphia (August 20-21, 2014). This in-depth conference will provide trail-blazing industry case studies and applications of eSource data. Expert will provide their Insights on:


1. Updated FDA guidelines

2. eSource’s impact on risk-based monitoring

3. Data synergy throughout the clinical trial chain

4. Data security and access protocol

5. Onsite management and compliance


View From the Hudson River


World Trade Center in Downtown NYC ©Target Health Inc.


ON TARGET is the newsletter of Target Health Inc., a NYC-based, full-service, contract research organization (eCRO), providing strategic planning, regulatory affairs, clinical research, data management, biostatistics, medical writing and software services to the pharmaceutical and device industries, including the paperless clinical trial.


For more information about Target Health contact Warren Pearlson (212-681-2100 ext. 104). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel or Ms. Joyce Hays. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website, and if you like the weekly newsletter, ON TARGET, you’ll love the Blog.


Joyce Hays, Founder and Editor in Chief of On Target

Jules Mitchel, Editor


Oxidative Stress


Oxidative stress can cause disruptions in normal mechanisms of cellular signaling.


Oxidation is the process of removing electrons from an atom or molecule. The result of this change can be destructive – rusting 1) ___ is a familiar result of oxidation. Here, oxygen is the responsible agent, but other oxidizing agents, such as chlorine, can be as harsh. Although we need oxygen to live, high concentrations of it are actually corrosive and toxic. We obtain energy by burning fuel with oxygen – that is, by combining digested 2) ___ with oxygen from the air we breathe. This is a controlled metabolic process that, unfortunately, also generates dangerous byproducts.


Production of reactive oxygen species (ROS) is a particularly destructive aspect of oxidative stress. Reactive oxygen species (ROS) are chemically reactive molecules containing oxygen. Such species include free radicals and peroxides. Normally, cells defend themselves against ROS damage with enzymes. The most important plasma antioxidant in humans is uric acid.


Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the formula C5H4N4O3. It forms ions and salts known as urates and acid urates such as ammonium acid urate. Uric acid is a product of the metabolic breakdown of purine nucleotides. High blood concentrations of uric acid can lead to gout. The chemical is associated with other medical conditions including diabetes and the formation of ammonium acid urate 3) ___ stones.


Free radicals are electronically unstable atoms or molecules capable of stripping electrons from any other molecules they meet in an effort to achieve stability. In their wake they create even more unstable molecules that then attack their neighbors in domino-like chain reactions. By the time a free radical chain fizzles out, it may have ripped through vital components of cells, causing extensive damage, similar to that caused by ionizing radiation.


Oxidative stress is the total burden placed on organisms by the constant production of free 4) ___ in the normal course of metabolism plus whatever other pressures the environment brings to bear (natural and artificial radiation, toxins in air, food and water; and miscellaneous sources of oxidizing activity, such as tobacco smoke).


Our bodies aren’t helpless in the face of these assaults. We have defenses against oxidative stress in the form of physical barriers to contain free radicals at their sites of production within cells; enzymes that neutralize dangerously reactive forms of oxygen; substances in our diets (such as vitamin C and vitamin E) that can “quench“ free radicals by donating electrons to them and cutting off the chain reactions early in their course; repair mechanisms to take care of oxidative damage to DNA, proteins and membranes; and complex stress responses that include programmed cell suicide if damage is too great.


A good case can be made for the notion that health depends on a balance between 5) ___ stress and antioxidant defenses. Aging and age-related diseases reflect the inability of our antioxidant defenses to cope with oxidative stress over time. The good news is that with strong antioxidant defenses, long life without disease should be possible. Environmental stress is one of the biggest causes of free radicals, which is a process where the body starts producing oxygen much faster. This process is referred to as oxidative stress. Oxidative stress is essentially an imbalance between the production of free radicals and the ability of the body to counteract or detoxify their harmful effects through neutralization by 6) ___.


There are a number of symptoms which could point towards oxidative stress and if left unchecked could hasten the aging process and also cause a number of neurodegenerative diseases and also a few cardiovascular diseases, as well as cancer. A few such diseases are:


1. Hyperoxia, which is excess oxygen or higher than normal partial pressure of oxygen. It refers to excess oxygen in the lungs or other body tissues, which can be caused by breathing air or oxygen at pressures greater than normal atmospheric pressure. This kind of hyperoxia can lead to oxygen toxicity.

2. Tissue injury

3. Irradiation


Oxidative stress leads to many pathophysiological conditions in the body. Some of these include neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease, gene mutations and cancers, chronic fatigue syndrome, fragile X syndrome, heart and blood vessel disorders, atherosclerosis, heart failure, heart attack and inflammatory diseases. Oxidative stress is thought to be linked to certain cardiovascular disease, since oxidation of LDL in the vascular endothelium is a precursor to plaque formation. More severe oxidative stress can cause cell death and even moderate oxidation can trigger apoptosis, while more intense stresses may cause necrosis.


Oxygen by-products are relatively unreactive but some of these can undergo metabolism within the biological system to give rise to these highly reactive oxidants. Not all reactive oxygen species are harmful to the 7) ___ body. Some of them are useful in killing invading pathogens or microbes. Free radicals can chemically interact with cell components such as DNA, protein or lipid and steal their electrons in order to become stabilized. This, in turn, destabilizes the cell component molecules which then seek and steal an electron from another molecule, therefore triggering a large chain of free radical reactions.


Every cell that utilizes enzymes and oxygen to perform functions is exposed to oxygen free radical reactions that have the potential to cause serious damage to the cell. Antioxidants are molecules present in cells that prevent these reactions by donating an electron to the free radicals without becoming destabilized themselves. An imbalance between oxidants and antioxidants is the underlying basis of oxidative stress. To counteract oxidative stress, the body produces an armory of antioxidants to defend itself. It’s the job of antioxidants to neutralize or ‘mop up’ free radicals that can harm our 8) ___ cells.


The body’s ability to produce antioxidants (its metabolic process) is controlled by genetic makeup and influenced by exposure to environmental factors, such as diet and smoking, pollution. Changes in lifestyles, which include more environmental pollution and less quality in our diets, expose us to more free radicals than ever before. The body’s internal production of antioxidants can be added to by increasing dietary intake of antioxidant foods.


Tomatoes containing a pigment called 9) ___ lycopene (responsible for the red color) are powerful antioxidants. Tomatoes in all their forms are a major source of lycopene, including tomato products like canned tomatoes, tomato soup, tomato juice and even ketchup. Lycopene is also highly concentrated in watermelon. Oranges, grapefruit, lemons and limes possess many natural substances that appear to be important in disease protection, such as carotenoids, flavonoids, terpenes, limonoids and coumarins. Together these phytochemicals act more powerfully than if they were given separately. It’s better to eat the fruit whole in its natural form, because some of the potency is lost when the juice is extracted.


Black tea, green tea and oolong teas have antioxidant properties. All three varieties come from the plant Camellia sinenis. Common brands of black tea do contain antioxidants, but by far the most potent source is green tea (jasmine tea) which contains the antioxidant catechin. Beta-carotene is an orange pigment that was isolated from carrots 150 years ago. It is found concentrated in deep orange and green vegetables (the green chlorophyll covers up the orange pigment). 10) ___Beta-carotene is an antioxidant that has been much discussed in connection with lung cancer rates.


Studies have shown that people who eat a diet that is rich in fruit and vegetables are less likely to get diseases, such as cancer, heart disease and stroke.


ANSWERS: 1) iron; 2) food; 3) kidney; 4) radicals; 5) oxidative;6) antioxidants; 7) body; 8) cells; 9) lycopene; 10) Beta-carotene


Otto Heinrich Warburg (1883-1970)


Otto Heinrich Warburg (October 8, 1883 – August 1, 1970), son of physicist Emil Warburg, was a German physiologist and medical doctor. Warburg was one of the 20th century’s leading biochemists and was awarded the Nobel Prize in 1931. In total, he was nominated an unprecedented three times for the Nobel Prize for three separate achievements.


Warburg’s father, Emil Warburg, was a member of the illustrious Warburg family of Altona, and had converted to Christianity reportedly after a disagreement with his Conservative Jewish parents. Emil was also president of the Physikalische Reichsanstalt, Wirklicher Geheimer Oberregierungsrat (True Senior Privy Counselor). His mother was the daughter of a Protestant family of bankers and civil servants from Baden. His much older cousin, also named Otto Warburg (1859-1938), was a German botanist, a notable industrial agriculture expert, as well as an active member of the Zionist Organization, for which he served as president from 1911-1921.


Warburg studied chemistry under the great Emil Fischer, and earned his Doctor of Chemistry in Berlin in 1906. He then studied under Ludolf von Krehl, and earned the degree of Doctor of Medicine in Heidelberg in 1911. Between 1908 and 1914, Warburg was affiliated with the Naples Marine Biological Station, in Naples, Italy, where he conducted research.


A lifelong equestrian, he served as an officer in the elite Uhlans (cavalry) on the front during the First World War, where he won the Iron Cross. Warburg later credited this experience with affording him invaluable insights into “real life“ outside the confines of academia. Towards the end of the war, when the outcome was unmistakable, Albert Einstein, who had been a friend of Warburg’s father Emil, wrote Warburg at the behest of friends, asking him to leave the army and return to academia, since it would be a tragedy for the world to lose his talents. Einstein and Warburg later became friends, and Einstein’s work in physics had great influence on Otto’s biochemical research.




Otto Warburg in 1931


While working at the Marine Biological Station, Warburg performed research on oxygen consumption in sea urchin eggs after fertilization, and proved that upon fertilization, the rate of respiration increases by as much as six fold. His experiments also proved iron is essential for the development of the larval stage.


In 1918, Warburg was appointed professor at the Kaiser Wilhelm Institute for Biology in Berlin-Dahlem (part of the Kaiser-Wilhelm-Gesellschaft). By 1931 he was named director of the Kaiser Wilhelm Institute for Cell Physiology, which was founded the previous year by a donation of the Rockefeller Foundation to the Kaiser Wilhelm Gesellschaft (since renamed the Max Planck Society). Warburg investigated the metabolism of tumors and the respiration of cells, particularly cancer cells, and in 1931 was awarded the Nobel Prize in Physiology for his “discovery of the nature and mode of action of the respiratory enzyme.“


When the Nazis came to power people of Jewish descent were forced from their professional positions. For some reason despite having a Jewish father Warburg was spared. By this time Warburg was studying cancer. While banned from teaching, because he was Jewish, he was allowed to carry on his research. In 1935, Hitler had a polyp removed from his vocal cords. It is believed that afterwards, he feared that could develop cancer, which may have allowed Warburg to survive. In 1941, Warburg lost his post briefly, when he made critical remarks about the regime but a few weeks later a personal order from Hitler’s Chancellery ordered him to resume work on his cancer research. Goring also arranged for him to be classified as one-quarter Jewish. It is believed that Warburg was so totally dedicated to his work that he was prepared not only to stay in Germany but also accept the Nazi treatment of his Jewish colleagues and his Jewish relatives. This was despite his having received an offer from the Rockefeller Foundation to continue to fund his work if he emigrated. In 1943 Warburg relocated his laboratory to the village of Liebenburg on the outskirts of Berlin to avoid ongoing air attacks. After the end of the Second World War he made inquiries about moving to the United States, but was turned down.


In 1944, Warburg was nominated for a second Nobel Prize in Physiology by Albert Szent-Gyorgyi, for his work on nicotinamide, the mechanism and enzymes involved in fermentation, and the discovery of flavin (in yellow enzymes). Some sources reported he was selected to receive the award that year, but was prevented from receiving it by Adolf Hitler’s regime, which had issued a bizarre decree in 1937 that forbade Germans from accepting Nobel Prizes. According to the Nobel Foundation, this rumor is not true; although he was considered a worthwhile candidate, he was not selected for the prize.


Three scientists who worked in Warburg’s lab, including Sir Hans Adolf Krebs, who went on to win the Nobel Prize. Among other discoveries, Krebs is credited with the identification of the citric acid cycle (or Szentgy?rgyi-Krebs cycle).


Warburg’s combined work in plant physiology, cell metabolism and oncology made him an integral figure in the later development of systems biology. He worked with Dean Burk in photosynthesis to discover the I-quantum reaction that splits the CO2, activated by the respiration. In 1924, Warburg hypothesized that cancer, malignant growth, and tumor growth are caused by tumor cells mainly generating energy (as e.g. adenosine triphosphate / ATP) by nonoxidative breakdown of glucose (a process called glycolysis) and the subsequent recycling of the metabolite NADH back to its oxidized form, for reuse in the glycolytic cycle to complete the process (known as fermentation, or anaerobic respiration). This is in contrast to “healthy“ cells, which mainly generate energy from oxidative breakdown of pyruvate. Pyruvate is an end product of glycolysis, and is oxidized within the mitochondria. Hence, and according to Warburg, cancer should be interpreted as a mitochondrial dysfunction. According to Warburg, the prime cause of cancer is the replacement of the respiration of oxygen in normal body cells by a fermentation of sugar. Warburg continued to develop the hypothesis experimentally, and held several prominent lectures outlining the theory and the data.


The concept that cancer cells switch to fermentation in lieu of aerobic respiration has become widely accepted, even if it is not seen as the cause of cancer. Some suggest the Warburg phenomenon could be used to develop anticancer drugs. Meanwhile, cancer cell glycolysis is the basis of positron emission tomography (18-FDG PET), a medical imaging technology that relies on this phenomenon.




Warburg’s grave in Berlin, Cemetery Dahlem


Warburg edited and had much of his original work published in The Metabolism of Tumours (1931) and wrote New Methods of Cell Physiology(1962). An unabashed anglophile, Otto Warburg was thrilled when Oxford University awarded him an honorary doctorate. He was awarded the Order Pour le Merite in 1952, and was known to tell other universities not to bother with honorary doctorates, and to ask officials to mail him medals he had been awarded so as to avoid a ceremony that would separate him from his beloved laboratory.


Warburg also wrote about oxygen’s relationship to the pH of cancer cells’ internal environments. Since fermentation was a major metabolic pathway of cancer cells, Warburg reported cancer cells maintain a lower pH, as low as 6.0, due to lactic acid production and elevated CO2. He firmly believed there was a direct relationship between pH and oxygen. When frustrated by the lack of acceptance of his ideas, Warburg was known to quote an aphorism he attributed to Max Planck: Science progresses not because scientists change their minds, but rather because scientists attached to erroneous views die, and are replaced. Seemingly utterly convinced of the accuracy of his conclusions, Warburg expressed dismay at the “continual discovery of cancer agents and cancer viruses“ which he expected to “hinder necessary preventative measures and thereby become responsible for cancer cases“.


In his later years, Warburg, to a large degree, prescient, was convinced that illness resulted from pollution; this caused him to become a bit of a health advocate. He insisted on eating bread made from wheat grown organically on land that belonged to him. When he visited restaurants, he often made arrangements to pay the full price for a cup of tea, but only to be served boiling water, from which he would make tea with a tea bag he had brought with him. He was also known to go to significant lengths to obtain organic butter, the quality of which he trusted.


When Dr. Josef Issels, who became famous for his use of nonmainstream therapies to treat cancer, was arrested and later found guilty of malpractice in what Issels alleged was a highly politicized case, Warburg offered to testify on Issels’ behalf at his appeal to the German Supreme Court. All of Issels’ convictions were overturned.


The Otto Warburg Medal is intended to commemorate Warburg’s outstanding achievements. It has been awarded by the German Society for Biochemistry and Molecular Biology (Gesellschaft fur Biochemie und Molekularbiologie) since 1963. The prize honors and encourages pioneering achievements in fundamental biochemical and molecular biological research. The Otto Warburg Medal is regarded as the highest award for biochemists and molecular biologists in Germany. It has been endowed with prize money, sponsored by the publishing company Elsevier/BBA.


First Drug Candidate From NIH Program Acquired by Biopharmaceutical Company


NIH and US government support are key factors for breakthroughs in science, medicine and health care. Target Health congratulates the NIH for this major milestone.


A drug candidate developed by researchers at the NIH’s National Center for Advancing Translational Sciences (NCATS) and its collaborators has been licensed to Baxter International’s BioScience business. The drug candidate, Aes-103, is the first specifically developed to target the underlying molecular mechanism of sickle cell disease. Baxter now will advance the clinical development activities required for regulatory approval and commercialization. To read more about NCATS and its TRND program, visit


This is the first time a company has acquired a drug candidate developed with NCATS’ Therapeutics for Rare and Neglected Diseases (TRND) program resources. Baxter International recently acquired AesRx, LLC, Newton, Massachusetts — the TRND program collaborator — including Aes-103. TRND and AesRx researchers worked together to develop Aes-103 through a Phase II clinical trial to evaluate safety and effectiveness. The trial data indicated that Aes-103 significantly reduced patients’ pain. Aes-103 works by binding directly to hemoglobin and changing its structure, thereby reducing the sickling of red blood cells. This structural change may lessen sickling-related complications in patients.


“This is a wonderful example of why NCATS was created,“ said NIH Director Francis S. Collins, M.D., Ph.D. “The progress made thus far in the development of Aes-103 demonstrates NCATS’ catalytic role in bringing together the necessary players, whether academic, nonprofit or industry, to overcome obstacles to translation and advance badly needed treatments to patients.“


Sickle cell disease disproportionately affects African-Americans and is considered both rare and neglected in the United States. African-Americans with sickle cell often face significant health disparities in clinical care. Life expectancy for people with sickle cell disease is only to mid- to late 40s. Sickle cell disease is a genetic blood disorder that affects millions worldwide, including approximately 100,000 people in the United States – among them, 1 in 500 African-Americans. Individuals living with sickle cell disease have defective hemoglobin, the protein in red blood cells that carries oxygen. This defect causes their cells to become rigid and crescent-shaped, blocking small blood vessels and causing inflammation, pain and strokes, and decreased blood flow.


Prior to AesRx’s collaboration with TRND researchers, and despite promising data on Aes-103, the company had difficulty securing private financing because potential investors lacked interest in funding an early-stage project that was considered too risky. AesRx did not have the resources to complete preclinical and early clinical development.


Currently, the only drug approved by the U.S. Food and Drug Administration (FDA) to treat sickle cell disease is hydroxyurea, a drug initially developed to treat cancer. However, the clinical utility of hydroxyurea is limited. Many individuals with sickle cell disease either do not respond to the drug, or they may experience undesirable side effects.


TRND researchers signed a collaborative agreement with AesRx in 2010 and established a project team made up of NCATS and AesRx scientists as well as a leading sickle cell disease clinical researcher at the National Heart, Lung, and Blood Institute (NHLBI). Other key project collaborators received support through NHLBI grants, the NIH Clinical Center and its pharmacy, and NCATS’ Bridging Interventional Development Gaps program. Aes-103 was licensed by AesRx from Virginia Commonwealth University, Richmond, where the compound was discovered.


In less than one year, the team completed the preclinical toxicology, chemistry, manufacturing, controls and regulatory studies necessary to support an investigational new drug (IND) application, which AesRx filed with the FDA. After IND clearance, Aes-103 moved into Phase I clinical trials in healthy volunteers and sickle cell disease patients in 2011 and into a Phase II trial in patients in 2013. The project results also helped AesRx obtain a Massachusetts Life Science Accelerator loan to support development of Aes-103.


Rehabilitation Helps Prevent Depression for those with AMD


Age-related macular degeneration (AMD) is a leading cause of vision loss in the United States. About 2 million Americans age 50 and over have vision loss from AMD, and about 8 million have an earlier stage of the disease, with or without vision loss. AMD causes damage to the macula, a spot near the center of the retina that is needed for sharp, straight-ahead vision. It can affect one eye or both, which is called bilateral AMD. As the disease progresses, it can cause a growing blurred area near the center of vision, and lead to difficulty with everyday activities, including the ability to drive, read, write, watch television, cook, and do housework.


Activities that used to be fun and fulfilling may begin to seem burdensome or even impossible. With loss of the ability to drive and navigate unfamiliar places, it becomes easier to stay at home than to see friends or meet new people. All of this can take a toll on mental health, and past studies have found that as many as one-third of people with bilateral AMD develop clinical depression.


A new study, published online in Ophthalmology( July 2014), shows that a type of rehabilitation therapy can cut this risk in half. The study was funded by the National Eye Institute (NEI), part of the National Institutes of Health. The trial recruited 188 participants with bilateral AMD from an ophthalmology practice affiliated with Wills Eye Hospital in Philadelphia. The participants were 84 years of age on average, 70% were women, and 50% lived alone. All had a best-corrected vision of less than 20/70. (A person with 20/70 vision sees an object from 20 feet away as clearly as a person with normal vision sees it at 70 feet away.) Each participant had mild depressive symptoms and was at risk for developing clinical depression, based on a nine-item depression subtest of the Patient Health Questionnaire, or PHQ-9.


During the trial, the participants had two visits with an optometrist, during which they were prescribed low-vision devices such as handheld magnifiers. After those initial visits, the participants were randomly split into two groups. One group received behavior activation from an occupational therapist specially trained in the approach. The occupational therapist worked with participants to guide them on using the low-vision devices, to make changes around the home (such as using brighter lights and high-contrast tape), to increase their social activities, and to help them set personal goals and break these down into manageable steps. The second group of participants served as a control group. They talked about their difficulties to a therapist, but did not receive behavior activation or low-vision occupational therapy. Both groups had six one-hour therapy sessions in their homes over a two-month period. All participants were allowed to take antidepressants, but less than 10% did so. All received medical management of AMD as prescribed by their primary eye care providers.


By four months, 12 participants in the control group and seven participants in the behavior activation group had withdrawn from the trial or passed away. Of the remaining 169 participants, 18 (23.4%) in the control group and 11 (12.6%) in the behavior activation group developed clinical depression, based on retesting with the PHQ-9. Behavior activation had the most benefit for participants with the worst vision (less than 20/100), reducing the risk of depression by about 60% compared to controls. When the data were adjusted for vision status, physical health and baseline PHQ-9 score, behavior activation reduced the risk of depression by 50% compared to the control treatment.


The authors hope the study will serve as a model for similar approaches to preventing and treating depression in AMD, although stronger links between primary eye care and mental health care workers would be needed to make behavior activation more widely available for AMD patients. Also, specialized instruction would also be needed for occupational therapists, who are not typically trained in behavior activation. The study is continuing to follow participants to see if the benefits of treatment are maintained out to one year.


TARGET HEALTH excels in Regulatory Affairs. Each week we highlight new information in this challenging area.


A Blueprint for Helping Children with Rare Diseases


Last week, Target Health obtained orphan drug designation on behalf of 2 clients. The first designation was for a rare GI tumor and the second was for an autoimmune disease that affects blood vessels. This makes a total of 13 orphan drug designation obtained by Target Health, with 2 of the drug products reaching the market. A 3rd product in Cystic Fibrosis was approved in 2012.


The following is from FDA Voice (July 8, 2014)


The U.S. Congress and the US FDA are committed to bring new therapies to patients with rare diseases, including children. Two years ago this week, Congress made another contribution to this effort by enacting the Food and Drug Administration Safety and Innovation Act (FDASIA). The law directs the FDA to take two actions to further the development of new therapies for children affected by rare diseases:


(1) to hold a meeting with stakeholders and discuss ways to encourage and accelerate the development of new therapies for pediatric rare diseases, and

(2) issue a report that includes a strategic plan for achieving this goal.


There are unique challenges when developing drugs, biological products and medical devices for the pediatric population. Not only is there the potential for children to respond differently to products as they grow but there are also additional ethical concerns for this patient population. But these challenges are further compounded when developing therapies for pediatric rare diseases. For example, rare disease product development, by definition, means there is only a small potential group of patients available to participate in clinical studies that can help determine whether a product is safe and effective.


In a FDASIA meeting in January, a variety of suggestions were provided on clinical trial design and data collection from hundreds of the participating stakeholders from academia; clinical and treating communities; patient and advocacy groups; industry and governmental agencies. These discussions helped inform aStrategic Plan for Accelerating the Development of Therapies for Pediatric Rare Diseases. It outlines how we plan to meet the following four objectives:


Enhance foundational and translational science. Goal is to fill essential information gaps through such measures as fostering the conduct of natural history studies for pediatric rare diseases and by identifying unmet pediatric needs in medical device development. FDA also plans to issue guidance for sponsors on common issues in rare disease drug development and to refine and expand the use of computational modeling for medical devices.


Strengthen communication, collaboration, and partnering. Robust cooperation within FDA, among agencies, governments and private entities is necessary to enable the exchange of information on the issues of developing treatments for pediatric rare diseases. Single entities by themselves usually don’t have sufficient resources or expertise to overcome the product development challenges posed by pediatric rare diseases.


Advance the use of regulatory science to aid clinical trial design and performance. Regulatory science helps develop new tools, standards, and approaches to assess the safety, efficacy, quality, and performance of all FDA-regulated products. FDA plans to facilitate better understanding of biomarkers and clinical outcome assessments that are useful for the development of treatments for pediatric rare diseases. FDA also plans to further develop the expedited approval pathway for medical devices intended to treat unmet medical needs; and use FDA’s web-based resources to update and expand awareness of issues involving the development of medical products for pediatric rare diseases.


Enhance FDA’s review process. This strategy includes fostering efforts to learn patients’ and caregivers’ perspectives and incorporating this information into medical product development. FDA plans to further develop and implement a structured approach to benefit-risk assessment in the drug review process and establish a patient engagement panel as part of the medical device advisory committee process.


The report notes the use of expedited programs to speed rare disease medical product development. But it’s important to note that FDA’s regulatory flexibility is reducing the number of approvals under one of these procedures: the accelerated approval program for drugs that treat serious conditions and that fill an unmet medical need based on a surrogate or intermediate endpoint (that is, a measure such as blood test or urine marker that is believed to be indicative of a disease state and treatment effect, but not demonstrative of a direct health gain to the patient). Most of the recent new drug approvals for rare diseases that would otherwise qualify for accelerated approval were given regular or “traditional“ approval instead. As a result, they weren’t required to do confirmatory trials to verify clinical benefit, as required under accelerated approval, because FDA decided that the evidence was already strong enough.


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