DPharm Disruptive Innovations Meeting in Boston – A Must

 

Disruptive Innovations will again be at The Fairmont Copley Plaza, Boston, MA this year (September 11-12, 2014). This is one of our favorite meetings of the year as we are always challenged by stimulating speakers from pharma and device companies, patients, regulators, clinical sites, etc.

 

Our friends and colleagues Andreas Koester, MD, PhD, VP, Clinical Trial Innovation & External Alliances, Janssen; Jeff Kasher, PhD, VP, Clinical Innovation & Implementation, Eli Lilly; Craig Lipset, MBA, Head of Clinical Innovation, R&D, Pfizer, Inc.; and Komathi Stem, Senior Director, Product Development, Innovation Lead, Genentech, are the Co-Chairs of the conference.

 

Jules Mitchel, MBA, PhD, President of Target Health, is on the Advisory Board and an active contributor to this conference since its inception in 2011. Dr. Mitchel will be presenting at 12 pm on Thursday in a session chaired by Komathi Stem (Genentech), entitled “Where Are They A Year Later?“ We plan to share very exciting news from our programs using Target e*CTR® (eClinical Trial record), our web-based (browser independent) novel and regulatory compliant eSource solution for clinical trials. As a full-service CRO, not only do we have to have robust technology solutions, we also have to get products approved by regulatory agencies.

 

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.

 

Joyce Hays, Founder and Editor in Chief of On Target

Jules Mitchel, Editor

 

New Study: Diseased Cells Synthesize Their Own Drug

 

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Illustration of cells (stock image). “We’re using a cell as a reaction vessel and a disease-causing defect as a catalyst to synthesize a treatment in a diseased cell,“ explained Professor Matthew Disney. Credit:© Jezper / Fotolia

 

In a new study that could ultimately lead to many new medicines, scientists from the Florida campus of The Scripps Research Institute (TSRI) have adapted a chemical approach to turn diseased cells into unique manufacturing sites for molecules that can treat a form of muscular 1) ___. “We’re using a cell as a reaction vessel and a disease-causing defect as a catalyst to synthesize a treatment in a diseased cell,“ said TSRI Professor Matthew Disney. “Because the treatment is synthesized only in diseased 2) ___, the compounds could provide highly specific therapeutics that only act when a disease is present. This means we can potentially treat a host of conditions in a very selective and precise manner in totally unprecedented ways.“ The promising research was published recently in the international chemistry journal Angewandte Chemie.

 

In general, small, low molecular weight compounds can pass the blood-brain 3) ___, while larger, higher weight compounds tend to be more potent. In the new study, however, small molecules became powerful inhibitors when they bound to targets in cells expressing an RNA defect, such as those found in myotonic dystrophy. Myotonic dystrophy type 2, a relatively mild and uncommon form of the progressive muscle weakening 4) ___, is caused by a type of RNA defect known as a “tetranucleotide repeat,“ in which a series of four nucleotides is repeated more times than normal in an individual’s genetic code. In this case, a cytosine-cytosine-uracil-guanine (CCUG) repeat binds to the protein MBNL1, rendering it inactive and resulting in RNA splicing abnormalities that, in turn, results in the disease.

 

In the study, a pair of small molecule “modules“ the scientists developed binds to adjacent parts of the defect in a living cell, bringing these groups close together. Under these conditions, the adjacent parts reach out to one another and, as Disney describes it, permanently hold hands. Once that connection is made, the small 5) ___ binds tightly to the defect, potently reversing disease defects on a molecular level. “When these compounds assemble in the cell, they are 1,000 times more potent than the small molecule itself and 100 times more 6) ___ than our most active lead compound,“ said Research Associate Suzanne Rzuczek, the first author of the study. “This is the first time this has been validated in live cells.“

 

The basic process used by Disney and his colleagues is known as “click chemistry“ — a process invented by Nobel laureate K. Barry Sharpless, a chemist at TSRI, to quickly produce substances by attaching small units or modules together in much the same way this occurs naturally. “In my opinion, this is one unique and a nearly ideal application of the process Sharpless and his colleagues first developed,“ Disney said. Given the predictability of the process and the nearly endless combinations, translating such an approach to cellular systems could be enormously productive, Disney said. RNAs make ideal targets because they are modular, just like the compounds for which they provide a molecular template. Not only that, he added, but many similar 7) ___ cause a host of incurable diseases such as ALS (Lou Gehrig’s Disease), Huntington’s disease and more than 20 others for which there are no known 8) ___, making this approach a potential route to develop lead therapeutics to this large class of debilitating diseases.

 

Click chemistry is a term applied to chemical synthesis tailored to generate substances quickly and reliably by joining small units together. Click chemistry is not a single specific reaction, but describes a way of generating products that follows examples in nature, which also generates substances by joining small modular units. Click chemistry has also been used for selectively labeling biomolecules within biological systems. A Click reaction that is to be performed in a living system must meet an even more rigorous set of criteria than in an in vitro reaction. It must be bioorthogonal, meaning the reagents used may not interact with the biological system in any way, nor may they be9) ___. The reaction must also occur at neutral pH and at or around body temperature. Most Click reactions have a high energy content. The reactions are irreversible and involve carbon-hetero atom bonding processes. An example is the Staudinger ligation of azides.

 

Click chemistry in combination with combinatorial chemistry, high-throughput screening and building chemical libraries speeds up new drug 10) ___ by making each reaction in a multistep synthesis fast, efficient and predictable. Mimicking nature in organic synthesis may facilitate the discovery of new pharmaceuticals given the large number of possible structures.

 

Click chemistry has widespread applications. Some of them are:

  • Two-dimensional gel electrophoresis separation
  • preparative organic synthesis of 1,4-substituted triazoles
  • modification of peptide function with triazoles
  • modification of natural products and pharmaceuticals
  • natural product discovery
  • drug discovery

 

Sources: The above article is based on materials from Scripps Research Institute and Wikipedia; Journal Reference: Suzanne G. Rzuczek, HaJeung Park, Matthew D. Disney. A Toxic RNA Catalyzes the In Cellulo Synthesis of Its Own Inhibitor. Angewandte Chemie International Edition, 2014; DOI: 10.1002/anie.201406465

 

ANSWERS: 1) dystrophy; 2) cells; 3) barrier; 4) disease; 5) molecule; 6) potent; 7) RNAs; 8) cures; 9) toxic; 10) discoveries

 

Karl Barry Sharpless PhD, Nobel Prize Winner (b. 1941 to Present)

 

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Dr. K. Barry Sharpless is an American chemist known for his work on stereoselective reactions. He earned a Ph.D in chemistry from Stanford University in 1968, and continued post-doctoral work at Stanford University (1968-1969) and Harvard University.(1969-1970). He holds honorary degrees from the Royal Institute of Technology, Stockholm (1995) Technical University of Munich (1995), Catholic University Louvain, Belgium (1996) and Weselyan University (1999). He was blinded in one eye during a lab accident in 1970, shortly after he arrived at MIT as an assistant professor. Sharpless has been a professor at the Massachusetts Institute of Technology (1970-1977, 1980-1990) and Stanford University (1977-1980) and currently holds the W. M. Keck professorship in chemistry at The Scripps Research Institute (1990- to Present).

 

Sharpless developed stereoselective oxidation reactions, and showed that the formation of an inhibitor with femtomolar potency can be catalyzed by the enzyme acetylcholinesterase, beginning with an azide and an alkyne. He discovered several chemical reactions which have transformed asymmetric synthesis from science fiction to the relatively routine, including aminohydroxylation, dihydroxylation, and the Sharpless asymmetric epoxidation. In 2001 he won a half-share of the Nobel Prize in Chemistry for his work on chirally catalysed oxidation reactions (Sharpless epoxidation, Sharpless asymmetric dihydroxylation, Sharpless oxyamination). The other half of the year’s Prize was shared between William S. Knowles and Ryoji Noyori (for their work on stereoselective hydrogenation). He also successfully epoxidized (using racemic tartaric acid) a C-86 Buckminster Fullerene ball, employing p-Cresol as solvent. More recently he has been an important figure in the new field of click chemistry. This involves a set of highly selective, exothermic reactions which occur under mild conditions; the most successful example is the azide alkyne Huisgen cycloaddition to form 1,2,3-triazoles.

 

Sharpless married Jan Dueser on 28 April 1965. They have three children; Hannah (b. 1976), William (b. 1978), and Isaac (b. 1980). [Editor’s note: Because of its unique style, we include, below, the Nobel Prize acceptance speech given by K. Barry Sharpless in 2001]:

 

The Nobel Prize in Chemistry 2001: William S. Knowles, Ryoji Noyori, K. Barry Sharpless

 

From 6th through 12th grades I attended a Quaker school on the Philadelphia city line. Twice a week the entire school attended Quaker Meeting, silent gatherings except when someone received a personal call to speak. I never got a call, but nonetheless my head was full: I thought about fishing and boats. Or else I thought about when next I could get from Philadelphia to our cottage on the New Jersey Shore in order to go out fishing in a boat. Beneath my picture in one high school yearbook it says, “I’m going to the Shore“. While I had an overwhelming passion for fishing, school I merely enjoyed and I never planned to be a scientist. In fact, passion, not planning, is the engine driving all my thought and action. The almost unimaginably good fortune of my youth was that other people made such very, very good plans and choices for me.

 

My parents selected the excellent Friends Central School where, fortuitously, Clayton Farraday was both a science teacher and the school’s beloved Mr. Chips. The counselors there decided, wisely, that I should attend a college rather than a large university, and I departed Philadelphia for Dartmouth College in the fall of 1959. Though literature courses there were my favorites, I was a pre-medical student solely because my parents always hoped that I’d become an MD like my father. Pre-meds majored in chemistry or biology, and between the two I leaned toward chemistry. I didn’t get really interested, however, until I had two semesters of organic my sophomore year from a young chemistry professor who chose me to do research in his lab. When I graduated Dartmouth a few years later, in 1963, the same prof called my next move, a PhD in organic chemistry instead of medical school. He even chose the graduate school I attended and my research supervisor there. Such a strong intervention in a student’s life is no doubt unusual, but the precipitating events were unusual, too.

 

Generally speaking, colleges have the best undergraduate teaching, and universities, whose labs are filled by graduate and post-graduate students, have the best research. When I arrived at Dartmouth College in 1959, the chemistry department had a graduate program, which meant great teachers who were just as good at research. However, the program was small, and only a master’s degree was awarded, so consequently professors were perpetually hungry for more manpower for their labs, more “hands“. Undergraduates who performed well in lab courses were actively recruited to do “real“ graduate- level research.

 

Thomas A. Spencer, a brand-new assistant professor of chemistry, arrived at Dartmouth when I did, and I was part of his research group for three years. Because Tom was (and still is) so smart and such a good chemist, he could recognize not just talent, but the potential to do something significant; because Tom was also born a great teacher, he was obliged to give a swift kick to my comfortable obliviousness. Fishing, now in the form of working all summer on charter boats, continued as my abiding passion, which meant I continued to need a wise person to make good decisions for me. If some variables in my adult life were changed, I might still have made it onto these pages, but it never would have happened without Tom Spencer.

 

Since some family background and professional activities (and lots more about fishing) are in the Nobel lecture that follows, and since the standard biographical folderol is most easily found online at www.scripps.edu/chem/sharpless/, I hope to provide a more interesting read with the highly subjective and largely unorthodox personal information that follows.

 

I met my future wife, Jan Dueser, at a beach party at San Gregorio, west across the foothills from Stanford University. I was a first-year graduate student, and she was a Stanford sophomore and, on that day, my roommate’s date. I admired her touch football form, and she entrusted me with her delicate wristwatch, which I lost in the sand. We were married about a year-and-a-half later, on April 28, 1965, my 24th birthday, at the Palo Alto courthouse. David Schooley, a fellow chemistry grad student and now a professor at University of Nevada, Reno, was our best man. Jan and I practiced with dogs before we had children; chemists still ask about our first, the black and enormous Lionel, a regular laboratory and classroom visitor at MIT. Our daughter Hannah (whose nickname “Pippi“, comes from “pipette“, not from Miss Longstocking) was born in 1976, and is a middle school teacher in Boston. To chemists who’ve attended my seminars, she is permanently six years old, the familiar Alice in Wonderland who gazes at the huge book of Looking Glass Sugars. William (“Will“) and Isaac (“Ike“) followed Hannah at two-year intervals. Both of our sons are still college undergraduates. None of our children has much interest in science, and I’m sorry, but not disappointed, that that is so.

 

 

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His passion for chemistry was preceded by a passion for fishing

 

With no children at home any more, dogs are, once again, our companions of choice – for play, for exercise and for hanging out with in bed. I haven’t gone fishing for probably over thirty years, but the ocean is still programmed into me like the birth stream of a salmon. One of the glories of moving to Scripps in 1990 has been seeing the Pacific Ocean every day, and, when its temperature reaches 70o (July or August), swimming in it every day as well. In windy New England I wind-surfed and we loved our little catamaran; San Diego’s sail-less ocean vistas still seem weird.

 

My most important award, the greatest honor I’ve ever received, and the grandest and most memorable occasions I’ve ever witnessed, are, of course, benefits of sharing the 2001 Nobel Prize in Chemistry. But other honors have peerless characteristics as well, notably:

 

The heaviest object in our bank deposit box is the 1995 King Faisal Prize for Science medal; the most beautiful one is the 1988 Prelog Medal from the Swiss Federal Institute of Technology (ETH). Its exquisite relief rendering of Old Vlado’s profile rivals the most beautiful portraits found on coins from antiquity, and the gold has a gorgeous, pliant, velvety warmth that has to be seen to be believed (by appointment only). A friend once asked, quite appropriately, if the portrait was of Alexander the Great. Three unique objects, and I treasure each one, celebrate the day in 1995 when I received an honorary doctorate from Stockholm’s Royal Institute of Technology. My only top hat, frequently brought out for guests to admire, bears the Institute’s seal; my only ring, always admired when I wear it, is a heavy gold band surrounded by a garland of leaves and acorns in deep relief. These two I share with all the Institute’s doctoral recipients, but I also have a large brass cannon shell casing, fired during the cannon salute that accompanied the conferring of the degree and the ceremonial placing of the hat on my head. The shell sits on my desk at home.

 

Only one award commemoration of mine is lettered on real vellum, and it is the largest one, as well: in both English and Hebrew the 1998 Harvey Science and Technology Prize of the Israel Institute of Technology, Haifa’s Technion, is proclaimed. In the category “news received most delightfully“, the winner is — an April, 1984, telephone call Jan took in a Jacksonville, Florida, hotel room all five of us were sharing while I attended a meeting. On the line from Washington, D.C. was my MIT colleague George Buchi, the most generous and thoughtful colleague I have ever known. George said he was calling because it was announced just minutes before that I had been elected to membership in the National Academy of Sciences. When Jan replied that she’d pass the message on, George said, no, she must go immediately to the meeting room and give me the message. Our children were too young to be left alone, especially since the meeting room was next to a swimming pool. I was giving my talk when I saw Jan and the three children, and all of them on tiptoes, enter the room and move along the back in the semi-darkness. She was looking for a familiar face, and she whispered the message when she found one. I stopped talking as Jan’s informant walked to the front of the room and asked for the lights to be brought up so he could make an important announcement. Why the audience was so enthusiastic I wasn’t quite sure. Not only did I not know I’d been nominated, I didn’t even know one had to be nominated. I thought the National Academy was something like a high-level appointed government advisory committee. Learning otherwise was a wonderful surprise.

 

Inaugural events always have special significance and vivid memories; these “firsts“ mean a lot to me: Receiving the first Paul Janssen Prize for Creativity in Organic Synthesis, presented by HRH Prince (now King) Albert of Belgium. Security forces were everywhere that day in 1986, and I asked Prince Albert if having to travel with such a large group wasn’t inconvenient. No, he replied, all those soldiers were required because I was an American – he didn’t need them.

 

Being Texas A & M’s first Barton Lecturer, 1997. Nothing is dearer me than having been selected by Sir Derek, my career-long scientific role model and mentor, to deliver the first edition of a lectureship endowed in his honor, the only Barton Lecture to take place before his death in 1998. Launching the University of Sydney’s Cornforth Foundation for Chemistry (which honors both Rita and Kappa) with the inaugural Cornforth lecture in 2002. Like Sir Derek, Sir John is one of our gods; I stand awed at having participated in these events honoring them. And, finally, if I had a crown, its jewels would be the 75-or-so former Sharpless Group members who are research professors. The training received in the group is neither predictable nor quantifiable; likewise, it is not intended to produce a product that, for example, industry wants. Since nothing original is intentionally discovered by scientists who cannot tolerate (indeed, they should welcome it) a high degree of uncertainty, group membership does not guarantee results. Because of the nature of our research, however, group members preselect themselves and possess a remarkably high degree of independence of thought as well as scientific motives tilted toward discovery, not reward. As a group, they hold superior standards for judging the significance of research, and I share with all them all of the glory that is a Nobel Prize.

 

Click, to play the game, “Eye of the Donkey“ based on a Nobel Prize

 

EBOLA

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NIH To Launch Human Safety Study of Ebola Vaccine Candidate

 

Initial human testing of an investigational vaccine to prevent Ebola virus disease is being initiated by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. The early-stage trial will begin initial human testing of a vaccine co-developed by NIAID and GlaxoSmithKline (GSK) and will evaluate the experimental vaccine’s safety and ability to generate an immune system response in healthy adults. Testing will take place at the NIH Clinical Center in Bethesda, Maryland.

 

The study is the first of several Phase 1 clinical trials that will examine the investigational NIAID/GSK Ebola vaccine and an experimental Ebola vaccine developed by the Public Health Agency of Canada and licensed to NewLink Genetics Corp. The others are to launch in the fall. These trials are conducted in healthy adults who are not infected with Ebola virus to determine if the vaccine is safe and induces an adequate immune response. In parallel, NIH has partnered with a British-based international consortium that includes the Wellcome Trust and Britain’s Medical Research Council and Department for International Development to test the NIAID/GSK vaccine candidate among healthy volunteers in the United Kingdom and in the West African countries of Gambia (after approval from the relevant authorities) and Mali. Additionally, the U.S. Centers for Disease Control and Prevention has initiated discussions with Ministry of Health officials in Nigeria about the prospects for conducting a Phase 1 safety study of the vaccine among healthy adults in that country.

 

The pace of human safety testing for experimental Ebola vaccines has been expedited in response to the ongoing Ebola virus outbreak in West Africa. According to the World Health Organization (WHO), more than 1,400 suspected and confirmed deaths from Ebola infection have been reported in Guinea, Liberia, Nigeria, and Sierra Leone since the outbreak was first reported in March 2014.

 

The investigational vaccine now entering Phase 1 trials was designed by Nancy J. Sullivan, Ph.D., chief of the Biodefense Research Section in NIAID’s Vaccine Research Center (VRC). She worked in collaboration with researchers at the VRC, the U.S. Army Medical Research Institute of Infectious Diseases, and Okairos, a Swiss-Italian biotechnology company acquired by GSK in 2013.

 

The NIAID/GSK Ebola vaccine candidate is based on a type of chimpanzee cold virus, called chimp adenovirus type 3 (ChAd3). The adenovirus is used as a carrier, or vector, to deliver segments of genetic material derived from two Ebola virus species: Zaire Ebola and Sudan Ebola. Hence, this vaccine is referred to as a bivalent vaccine. The Zaire species of the virus is responsible for the current Ebola outbreak in West Africa. The vaccine candidate delivers one part of Ebola’s genetic material to human cells, but the adenovirus vector does not replicate. Rather, the Ebola gene that it carries allows the cells of the vaccine recipient to express a single Ebola protein, and that protein prompts an immune response in the individual. It is important to know that the Ebola genetic material contained in the investigational vaccine cannot cause a vaccinated individual to become infected with Ebola.

 

The Phase 1 clinical trial, called VRC 207, will be led by principal investigator Julie E. Ledgerwood, D.O., chief of the VRC’s clinical trials program, and will be conducted among 20 healthy adults ages 18 to 50 years. Participants will be divided into two groups of 10 participants each. One group will receive an intramuscular injection of the NIAID/GSK experimental vaccine. The second group will receive a single injection of the same vaccine but at a higher dose. A number of safety features are built into the study’s design, including daily and weekly reviews of patient data by clinical staff and the study protocol team. Additionally, the trial features a staged enrollment plan that requires interim safety reviews after three participants have been vaccinated and have undergone three days of follow up before enrolling additional study participants into the group. Participants in both groups will be seen and evaluated by clinical staff nine times over a 48-week period.

Shared Biology of Human, Fly and Worm Genomes

 

According to an article published online in Nature (28 August 2014), researchers analyzing human, fly, and worm genomes have found that these species have a number of key genomic processes in common, reflecting their shared ancestry. The findings offer insights into embryonic development, gene regulation and other biological processes vital to understanding human biology and disease. The studies highlight the data generated by the modENCODE Project and the ENCODE Project, both supported by the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health. Integrating data from the three species, the model organism ENCyclopedia Of DNA Elements (modENCODE) Consortium studied how gene expression patterns and regulatory proteins that help determine cell fate often share common features. Investigators also detailed the similar ways in which the three species use protein packaging to compact DNA into the cell nucleus and to regulate genome function by controlling access to DNA.

 

Launched in 2007, the goal of modENCODE is to create a comprehensive catalog of functional elements in the fruit fly and roundworm genomes for use by the research community. Such elements include genes that code for proteins, non-protein-coding genes and regulatory elements that control gene expression. The current work builds on initial catalogs published in 2010. The modENCODE projects complement the work being done by the ENCyclopedia Of DNA Elements (ENCODE) Project, which is building a comprehensive catalog of functional elements in the human and mouse genomes.

 

In one study, scientists led by Dr. Gerstein and others, analyzed human, fly and worm transcriptomes, the collection of gene transcripts (or readouts) in a genome. They used large amounts of gene expression data generated in the ENCODE and modENCODE projects — including more than 67 billion gene sequence readouts — to discover gene expression patterns shared by all three species, particularly for developmental genes. Investigators showed that the ways in which DNA is packaged in the cell are similar in many respects, and, in many cases, the species share programs for turning on and off genes in a coordinated manner. More specifically, they used gene expression patterns to match the stages of worm and fly development and found sets of genes that parallel each other in their usage. They also found the genes specifically expressed in the worm and fly embryos are re-expressed in the fly pupae, the stage between larva and adult.

 

The authors also found that in all three organisms, the gene expression levels for both protein-coding and non-protein-coding genes could be quantitatively predicted from chromatin features at the promoters of genes. A gene’s promoter tells the cell’s machinery where to begin copying DNA into RNA, which can be used to make proteins. DNA is packaged into chromatin in cells, and changes in this packaging can regulate gene function. Another group of scientists investigated how chromatin is organized and how it influences gene regulation in the three species. Using both modENCODE and ENCODE data, scientists compared patterns of modifications in chromatin that are needed for the cell to access the DNA inside, and the changes in DNA replication patterns as a result of these modifications. The investigators discovered that many features of chromatin were similar in all three species.

 

In a third study, similarities in genome regulation were explored. The study focused on transcription-regulatory factors, key protein regulators that determine which progenitor cells eventually become skin cells and kidney cells and eye cells. These are the key coordinators – they bind to switches that control a cell’s fate and one of the big questions in genomics is to determine what factors work together to turn on which genes. Investigators found that the transcription factors tend to bind to similar DNA sequences in the three species’ genomes, indicating that “the general properties of how regulatory information is laid out in the genomes are conserved in the three species,“ Dr. Snyder noted. “The general principles of regulation are more or less similar.“ Still, they found differences as well. The transcription factors bind very few of the same targets across species, and they are mostly expressed at different times.

 

FDA Approves Keytruda for Advanced Melanoma

 

Melanoma, which accounts for approximately 5% of all new cancers in the United States, occurs when cancer cells form in skin cells that make the pigment responsible for color in the skin. According to the National Cancer Institute, an estimated 76,100 Americans will be diagnosed with melanoma and 9,710 will die from the disease this year.

 

The FDA has granted accelerated approval to Keytruda (pembrolizumab) for treatment of patients with advanced or unresectable melanoma who are no longer responding to other drugs. Keytruda is the first approved drug that blocks a cellular pathway known as PD-1, which restricts the body’s immune system from attacking melanoma cells. Keytruda is intended for use following treatment with ipilimumab, a type of immunotherapy. For melanoma patients whose tumors express a gene mutation called BRAF V600, Keytruda is intended for use after treatment with ipilimumab and a BRAF inhibitor, a therapy that blocks activity of BRAF gene mutations.

 

The five prior FDA approvals for melanoma include: ipilimumab (2011), peginterferon alfa-2b (2011), vemurafenib (2011), dabrafenib (2013), and trametinib (2013).

 

The FDA granted Keytruda breakthrough therapy designation because the sponsor demonstrated through preliminary clinical evidence that the drug may offer a substantial improvement over available therapies. It also received priority review and orphan product designation. Priority review is granted to drugs that have the potential, at the time the application was submitted, to be a significant improvement in safety or effectiveness in the treatment of a serious condition. Orphan product designation is given to drugs intended to treat rare diseases.

 

The FDA action was taken under the agency’s accelerated approval program, which allows approval of a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients. This program provides earlier patient access to promising new drugs while the company conducts confirmatory clinical trials. An improvement in survival or disease-related symptoms has not yet been established.

 

Keytruda’s efficacy was established in 173 clinical trial participants with advanced melanoma whose disease progressed after prior treatment. All participants were treated with Keytruda, either at the recommended dose of 2 milligrams per kilogram (mg/kg) or at a higher dose of 10 mg/kg. In the half of the participants who received Keytruda at the recommended dose of 2 mg/kg, approximately 24% had their tumors shrink. This effect lasted at least 1.4 to 8.5 months and continued beyond this period in most patients. A similar percentage of patients had their tumor shrink at the 10 mg/kg dose.

 

Keytruda’s safety was established in the trial population of 411 participants with advanced melanoma. The most common side effects of Keytruda were fatigue, cough, nausea, itchy skin (pruritus), rash, decreased appetite, constipation, joint pain (arthralgia) and diarrhea. Keytruda also has the potential for severe immune-mediated side effects. In the 411 participants with advanced melanoma, severe immune-mediated side effects involving healthy organs, including the lung, colon, hormone-producing glands and liver, occurred uncommonly.

 

Keytruda is marketed by Merck & Co., based in Whitehouse Station, New Jersey.

 

Delicious Sauce for Salmon (Hot or Cold)

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Ingredients

1/2 cup sour cream

1/2 cup tofutti (low calorie cream cheese)

2 Tablespoons chopped fresh chives

2 teaspoons red onion, chopped

1 teaspoon fresh dill, chopped

(optional)1 teaspoon prepared mustard (out of jar)

1 teaspoon turmeric

4 or 5 fresh figs, cut in half (figs are at their plump peak now, and really luscious)

1 cup fresh seedless grapes (red or green), cut in half

Splash of white wine (not cooking wine).  Use whatever wine you’re planning to drink.  This is to slightly thin out the sauce

 

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Get your ingredients all lined up ©Joyce Hays, Target Health Inc.

 

Directions

 

1. In a medium size pan, mix the sour cream and the tofutti until well blended.

2. Add the chopped chives, red onion, chopped dill, mustard and turmeric. Mix very well until all ingredients are incorporated.

3. Now add the grapes and figs and stir.

 

 

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4. Turn a medium flame on and warm up the sauce. While stirring, add a splash of white wine, just to thin out the sauce a bit.

5. Add a dollop on top of each serving of salmon and sprinkle a little of the dill on top.

 

Enjoy!

 

 

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I decided to heat and serve the salmon in the same pan, which I brought to the table.

 

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No left-overs with this recipe

 

Serve your salmon with this sauce and a sprinkling of dill on top

 

 

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We’re still enjoying this icy Sauvignon Blanc from New Zealand.  I used a splash of this for the sauce.  © Joyce Hays, Target Health Inc.

 

The fresh salmon from Dean & Deluca, was sauteed on both sides. I do the skin side up first, very quickly and then turn the skin side down and saute that a little longer, leaving the center pink and nearly raw.

 

I had a big batch of home-made brown lentils frozen in the fridge and thawed some out, then heated them to serve with the salmon. As you can see the (recipe) sauce was spooned on top of the salmon with a sprinkling of fresh chopped dill on top. Mmmmm delicious! Very healthy too, with all the Omega-3s and valuable potassium for heart healthy people. My dear husband said, This is the best sauce you have ever made!  He insisted that I change the title of this piece from Simple Sauce to Delicious Sauce.

 

Although, we had the oaky Sauvignon Blanc with salmon topped with dill sauce, that you see above, we’ve discovered a red cab that works very well with a rich fish like salmon or tuna.

 

This past week, at db Bistro in Manhattan (highly recommend this delightful intimate Daniel Boulud restaurant), we had a wonderful time with a dear friend and colleague and learned from the sommelier there that a cabernet (2011) from Hall Vineyards in Napa Valley, was well suited to the fish we were ordering, as well as for meat. We shared a bottle and discovered (for us) a new wine, which we have ordered but hasn’t been delivered yet. Couldn’t find it in NY so it’s being shipped from CA. This Hall cab intrigues your nose. At the first sip, its lightness belies the full throat heat that lingers, in a wonderful after-taste. I bought a case at the WineExchange.com and it was the last bottle of 2011. There are still a few bottles on Amazon. The word must be out.

 

Have still not completely adjusted to NY after a memorable vacation in Santa Fe. But dinner with our friend at db Bistro helped to get me back into a NY state of mind.

 

From Our Table to Yours!

 

Bon Appetit !