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Hitting the Road

Train station entrance

(John St John/Flickr)

30 July 2015. Science and Enterprise is taking a mid-Summer break starting tomorrow, 31 July, through Monday, 3 August. We’ll resume our regular posting on Tuesday, 4 August.

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Trial Shows Weekly Growth Hormone Drug Effective, Safe

Child's feet


30 July 2015. Results of an intermediate-stage clinical trial show a drug candidate to treat growth hormone deficiency in children given once a week, works about as well as a current therapy requiring a daily injection. The results were released by Ascendis Pharma A/S, a specialty pharmaceutical company in Copenhagen, Denmark that conducted the trial.

Growth hormone deficiency occurs when the pituitary gland, located at the base of the brain, does not make enough growth hormone for a child to grow normally. Children with growth hormone deficiency often have a short stature, metabolic difficulties, and slower cognitive development, leading to a poor quality of life. Growth hormone deficiency can lead to delayed puberty, if left untreated.

Treatments today require daily injections of human growth hormone over long periods of time. The daily injection requirement often puts emotional burdens on parents and difficulties keeping with the daily injection schedule.

Ascendis Pharma develops prodrugs, inactive precursor compounds derived from active drug molecules that require exposure to enzymes or other chemicals in the body to activate. The company’s TransCon technology produces prodrugs designed to release proteins, peptides, or small molecules over an extended period of time. The technology includes a linker that responds to pH levels and temperature to release the active ingredients over a specified period, as well as a carrier designed to release its payloads either locally or systemically.

The clinical trial tested TransCon Growth Hormone, Ascendis’s treatment candidate for human growth hormone deficiency in children, formulated as an injection given once a week, against Genotropin, a current drug given daily. Both treatments are administered with an injection under the skin. The 53 participants were children in Europe and Egypt, ages 3 to 12, with growth hormone deficiency. The children enrolled in the trial were randomized to receive one of three dosage levels of TransCon Growth Hormone or Genotropin, over a 26-week period.

The trial looked primarily at the safety and tolerability of TransCon Growth Hormone, including number of serious adverse reactions, incidence of human growth hormone antibodies, and injection site reactions. The results show no serious adverse or unexpected reactions related to the drug. In addition, injection site reactions were mild and similar to those fond with Genotropin. And incidences of  human growth hormone antibodies were found to be similar to those generally reported for daily growth hormone injections.

The study also measured changes in height velocity, or rate of growth in height, which the researchers found for TransCon Growth Hormone at all three dosage levels to be similar to Genotropin. Likewise, concentrations of human growth hormone in the blood and increases in levels of insulin-like growth factor-1 — a hormone that contributes to bone and tissue growth — were similar between individuals receiving TransCon Growth Hormone and Genotropin, or consistent with expectations.

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Fibers Like Wool Yarn Devised from Animal Gelatin

Rolls of yarn

Rolls of yarn made from animal gelatin (ETH Zurich)

30 July 2015. A materials science doctoral student in Switzerland developed a process for converting animal gelatin into a fiber similar to yarn from high-quality wool. Philipp Stössel, in the Functional Materials Lab at ETH Zurich, a science and technology university, led the team that published its findings in a recent issue of the journal Biomacromolecules (paid subscription required).

Stössel, with colleagues at ETH Zurich and EMPA – Swiss Federal Laboratories for Materials Science and Technology, sought new methods for producing fibers for commercial-quality fabrics from natural and abundant raw materials. While wool and cotton continue to be popular with consumers, synthetic fibers take a large and growing segment of the global fiber market estimated at 70 million metric tons traded each year.

The researchers aimed to produce a bio-sourced substitute for merino wool, a variety of wool from merino sheep raised in mountain regions of New Zealand. Merino wool is lightweight natural fiber, yet can still provide insulation for cold weather garments, making it popular in performance sportswear.

The team chose animal gelatin as the source for their new fiber. Gelatin is a product of collagen, found in connective tissue skin, cartilage, and bones, and produced in abundance as discarded waste products in meat-packing plants. Stössel discovered that by adding the organic solvent isopropyl to a heated solution of water and gelatin, proteins from the gelatin separated and accumulated at the bottom of the container, making them easy to remove.

The researchers designed a process for removing the separated gelatin proteins and immediately converting them into fibers. The process uses multiple syringes that extract the accumulated proteins, and under even pressure pull out continuous filaments. The filaments are collected on Teflon-coated rolls in an ethanol bath that keeps the filaments separate while hardening.

The process yields porous filaments 25 micrometers in diameter at a rate of 200 meters a minute and produced 1,000 filaments that Stössel hand-spun into a 2-ply yarn for weaving into a fabric. The filaments and yarn are smooth, like merino wool, not rough and scaly like ordinary wool that feels itchy when worn directly over skin. Electron microscope images show the interior of the fibers has numerous pores and cavities that provide insulation for cold weather wear.

That process, however, also yields a fiber that breaks down in water, a result of gelatin’s solubility. The researchers used a series of treatments, starting with epoxy to bind together the gelatin components, followed by exposure to formaldehyde gas and lanolin infusions. Stössel says in an ETH Zurich statement that the fiber is still not as water resistant as natural sheep’s wool, but he plans to address this issue in his doctoral dissertation, currently being written.

To demonstrate its commercial potential, the team produced a glove from the yarn produced in the lab. The researchers applied for a patent on their process, and are seeking partners and financing for commercialization. The Functional Materials Lab that conducted the research has a track record of commercializing its discoveries, with five spin-off companies.

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Opioid Overdose Nasal Spray Cleared for FDA Review

Spilled pills


29 July 2015. Indivior plc, a pharmaceutical company in the U.K. specializing in addiction therapies, received notice that the U.S. Food and Drug Administration accepted the company’s new drug application and is beginning review of Indivior’s opioid overdose treatment formulated as a nasal spray. The FDA also granted Indivior, in Slough, U.K., priority review status for the nasal spray, which is expected to expedite its review.

Opioids work by reducing the intensity of pain signals to the brain, particularly regions of the brain controlling emotion, which reduces effects of the pain stimulus. Examples of leading opioid prescription pain medications are hydrocodone, oxycodon, morphine, and codeine.

Abuse of opioid pain killers is described by Centers for Disease Control and Prevention as a growing epidemic, fueled in part by growing numbers of prescriptions written for pain killing drugs. CDC reports that in 2012, physicians in the U.S. wrote 259 million prescriptions for pain killers, enough for one bottle of pills for every adult in the country. As of July 2014, according to the CDC, 46 people die each day in the U.S. from an overdose of prescription pain killers. The 10 states with the highest rates of prescriptions for pain killers, says CDC, are in the South.

The treatment candidate contains the opioid overdose antidote naloxone, now administered by physicians or emergency medical technicians as an injection, but can also be given by family members or home health care givers. Naloxone activates and binds to opioid receptors in the brain to reverse the effects of natural and synthetic opioids, and is considered the standard treatment for an opioid overdose.

Indivior is a developer of treatments for opioid dependence or overdose, including current products with naloxone. The nasal spray contains naloxone, but formulated to be quickly absorbed through mucous membranes in the nose. The drug is expected to be packaged in pre-measured single-dose containers, designed for use by people with minimal training to help overdose victims in an emergency. The company says clinical trials of the nasal spray are completed.

FDA designates new drugs for priority review if they’re considered significant improvements in safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions when compared to standard applications. Priority reviews make it possible for FDA to complete its review in 6 months compared to a typical 10 month standard review. However, priority reviews do not change the evaluation standards, nor do they affect the length of clinical trial periods.

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Crop Biotech Acquires Genomic Engineering Technology

Wheat plants

Shree Krishna Dhital (Wikimedia Commons)

29 July 2015. Calyxt Inc., a biotechnology company developing new varieties of food crops, is licensing technology from University of Minnesota for more efficient modification of plant genomes. Financial details of the agreement between Calyxt, in New Brighton Minnesota, and the university were not disclosed.

Calyxt — until recently known as Cellectis Plant Sciences — designs new types of food crops aimed at improving their health and nutritional qualities. The company’s product pipeline includes reduced transfat soybean oil, canola oil with lower saturated fats, and reduced gluten wheat using genomic editing and engineering tools created internally and in labs at University of Minnesota.

The new agreement gives Calyxt an exclusive worldwide license to genomic editing technology known as homologous recombination, a process for exchanging genetic code sequences between identical or similar DNA molecules, used for repair or replication of DNA. The licensed technology performs homologous recombination by harnessing geminiviruses, plant viruses with single strands of DNA.

The technology was developed in the lab of Dan Voytas, a plant biologist at University of Minnesota, as well as chief scientists at Calyxt. At the university, Voytas’s lab conducts research on homologous recombination, seeking more precise tools for genomic insertions, substitutions, and deletions to produce crops for food, plastics, and medicines. In a paper published in January 2014, Voytas with lab colleague Nicholas Baltes and others showed geminiviruses could be used as a delivery mechanism for genome-editing enzymes. Voytas and Baltes are named as inventors on the patent for the technology licensed from the university.

Calyxt in April licensed CRISPR technology from Voytas’s lab, short for clustered, regularly interspaced short palindromic repeats, applied to genomic engineering of plants. CRISPR is adapted from a natural process used by bacteria to protect against attack by viruses, where a protein that deactivates or replaces genes binds to targeted RNA molecules generated by the genome. The RNA molecules then guide the editing protein to specific genes needing changes.

The company is also working with existing genome editing techniques, including zinc finger nucleases, proteins of short-chain amino acids that make it possible to modify DNA sequences through corrections or insertions into those sequences. Another genomic-editing tool used by Cellectis is transcription activator-like effector nucleases or TALENs, programmable proteins that bind to DNA sequences and like CRISPR can address specific targets in the genome.

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Patent Awarded for Fractal Connections in Implants

Richard Taylor

Richard Taylor (University of Oregon)

28 July 2015. Electronic microcircuits designed to resemble fractals in nature used in implanted medical devices received a patent from the U.S. Patent and Trademark Office. Patent number 9,079,017 was awarded on 14 July 2015 to physicist and materials scientist Richard Taylor at University of Oregon and Simon Brown at University of Canterbury in New Zealand. The patent is assigned to both institutions.

Fractals are never-ending complex patterns, generated by repeating simple processes through a constant feedback loop. In nature, fractal patterns are common and familiar, found in trees, clouds, and lightning, as well as biological networks of blood vessels and neurons or nerve cells.

Taylor — professor of physics, psychology, and art, as well as director of the Materials Science Institute at University of Oregon in Eugene — studies microcircuits that bridge the dimensional gap limiting connections between biological networks with fractal designs and electronic circuits with more predictable one-dimensional patterns. In retinal implants to overcome failing eyesight from macular degeneration, for example, less than 10 percent of electrodes appear to interact with neurons in the eye. Likewise, electronic sensors are currently able to read signals from no more than 100 neurons in the cortical column in the brain at any one time, despite there being thousands of neurons in that region.

In their labs, Taylor and Brown develop technologies to grow nanoscale circuits with metal nanoparticles that self-assemble into fractal patterns resembling the branches found in biological networks. Interconnections with these fractal-inspired networks detect and monitor nerve signals, as well as induce signals and control their transmission through networks of neurons. When implanted, these circuits would encourage acceptance with glial cells, the cells in the brain supporting neurons, rather than stimulate rejection by the body’s immune system.

The patent covers fractal interfaces for connecting any electronics to any nerve. The document describes the scope as fractal-inspired interconnections designed not just for retinal implants, but for any neural networks in the body, as well as artificially grown neurons. In addition, the patent covers fractal connections with neuronal networks in any organisms, including parts of severed nerves in petri dishes.

Taylor says in a university statement the technology is not quite ready for practical applications, requiring “at least another couple of years of basic science before moving forward.” University of Oregon’s technology transfer office, however, already offers the invention for licensing.

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Computer Model Predicts Protein Binding to DNA, RNA

DNA illustration

(National Heart, Lung, and Blood Institute, NIH)

28 July 2015. Geneticists and computer scientists wrote a machine-learning model for predicting the way proteins bind to genetic material, and uncovering mutations causing disease. The team led by Brendan Frey with the Canadian Institute for Advanced Research in Toronto published its findings yesterday in the journal Nature Biotechnology (paid subscription required).

Frey and other authors founded Deep Genomics, a start-up company in Toronto to commercialize their research applying machine learning to uncover genetic abnormalities.

The researchers, from University of Toronto and Children’s Hospital Medical Center in Cincinnati, sought an automated method for discovering disruptions in the way cells function caused by abnormal variations in an individual’s genetic code or the way that code is expressed. This understanding can help medical scientists develop much more precise therapies that address these specific anomalies, a strategy known as precision medicine.

The researchers used an emerging computer modeling technique called deep learning to analyze and create an understanding of the complex processes proteins in the body bind with DNA in the genetic code and RNA expressing the code. Deep learning makes it possible for machines to discern underlying patterns in relationships, and build those relationships into knowledge bases applied to a number of disciplines. Advances in deep learning developed at Canadian Institute for Advanced Research, for example, are applied to neural network models employed by Google and Facebook.

In this case, the deep-learning algorithms enable the researchers to predict the binding of proteins with specific sequences of DNA and RNA that result from mutations in the genetic code. The model tests the DNA or RNA sequence against the chemistry of proteins and computes the likelihood of proteins binding to that sequence. Where mutations alter the sites where proteins can bind offers a predictor of disrupted cellular functions and a higher probability of disease.

The team developed the model into a stand-alone software tool known as DeepBind that the authors say can automatically analyze millions of sequences at a time. In tests of the model reported in the journal paper, the team uncovered new details about hemophilia and hypercholesterolemia, inherited conditions causing blood clotting problems and high cholesterol respectively, as well as some forms of cancer and mutations related to disorders in the cerebral cortex.

Deep Genomics, a spin-off company from University of Toronto where Frey is on the engineering faculty, is commercializing deep learning technologies applied to genomics. Frey is the company’s CEO, with co-authors Andrew DeLong and Babak Alipanahi serving on the company’s scientific team. The first product from Deep Genomics is Spidex, a data set of genetic variations with predicted effects on RNA splicing, modifications of RNA before it becomes messenger RNA that carries signals to cells. The company is making Spidex available free of charge for non-commercial use.

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FDA Clears Trial of Fibrosis Drug for Muscular Dystrophy

Muscle tissue cross section

Cross-section of muscle tissue from a person with Duchenne muscular dystrophy shows extensive replacement of dark colored muscle fiber with light-colored adipose or fat cells. (Centers for Disease Control and Prevention)

24 July 2015. Biotechnology company Fibrogen Inc. says the U.S. Food and Drug Administration approved an application to test its fibrosis drug candidate in patients with Duchenne muscular dystrophy. The company says FDA’s approval was part of a new drug application for its candidate, code-named FG-3019, already in intermediate-stage clinical trials as a therapy for various fibrotic diseases.

Duchenne muscular dystrophy is a rare genetic disorder resulting in muscle degeneration and weakness, primarily in the shoulders, arms, hips, and thighs. The disease affects mainly boys starting at age 3 to 5, and caused by a defective gene that fails to produce the protein dystrophin for strengthening muscle fiber and protecting muscles from injury.

FG-3019 is an engineered antibody designed to block the activity of connective tissue growth factor or CTGF, a protein secreted by cells that provides structure and support for those cells. While CTGF plays an important role in skeletal development and wound repair, it is also associated with fibrosis, the growth of excess tissue that occurs in response to injury or damage, and is often referred to as scarring. The excess tissue growth, however, can happen internally as well with damaging effects on organs in disorders such as liver fibrosis and idiopathic pulmonary fibrosis, as well as some forms of cancer.

In Duchenne muscular dystrophy, says the company, the lack of dystrophin leads to diminished muscle function that correlates with the extent of intra-muscular fibrosis. Fibrogen says it studied the role of CTGF in Duchenne muscular dystrophy for 10 years, and believes CTGF prevents the repair of damaged muscles in people with the disorder. In preclinical studies, says Fibrogen, FG-3019 reduced muscle fibrosis and improved muscle function.

FG-3019 is currently in intermediate stage trials for idiopathic pulmonary fibrosis that affects the lungs and liver fibrosis that results from chronic hepatitis B infections. The company says FG-3019 reversed fibrosis in a sizable number of patients enrolled in the idiopathic pulmonary fibrosis trial. The company is also enrolling participants for a trial to test FG-3019 among patients with pancreatic cancer.

Fibrogen, in San Francisco, says it shared its preclinical findings and met with the TREAT-NMD Advisory Committee for Therapeutics, a group that reviews and provides guidance on drug development research for neuromuscular diseases. The meetings with this committee, says the company, led to refinements in its clinical trial design. Fibrogen adds the advisory committee and other experts support plans for the clinical trial planned for enrollment later this year.

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Allergan Acquires Depression Therapy Developer for $560M

Man in pain

(Lloyd Morgan, Flickr)

27 July 2015. Pharmaceutical maker Allergan plc is acquiring Naurex Inc., a designer of fast-acting therapies for depression and other neurological disorders, for $560 million. The deal covers Naurex’s products now in clinical trials, with the company’s technology platform and preclinical research spun-off into a new enterprise.

Naurex, a spin-off company from Northwestern University in Evanston, Illinois, develops drugs for diseases of the central nervous system that stimulate N-Methyl-D-aspartate (NMDA) receptors, molecules found in synapses, a part of nerve cells that permit sending and receiving of signals. NMDA receptors help keep synapses flexible, which affects memory, learning, and development of the central nervous system. Naurex uses this platform to discover drugs to treat mood and anxiety disorders, cognitive disorders, neurodegenerative diseases, developmental disorders, neuropathic pain, and addiction.

Naurex’s lead product is rapastinel, being tested as a back-up drug for patients with major depressive disorder not responding to earlier antidepressants. In an intermediate-stage trial, a single dose of rapastinel was tested against a placebo with 300 patients who did not respond to earlier antidepressants. The company says initial findings show the drug acted quickly, within 24 hours, to reduce depression scores on the standard Hamilton Depression Rating Scale, compared to patients receiving the placebo, with results lasting several days.

Naurex says rapastinel is ready for late-stage clinical trials as a once-a-week intravenous therapy. The drug is also in trials as a treatment for obsessive-compulsive disorder.

A more advanced product, code-named NRX-1074, is a follow-on medication to rapastinel, and while chemically similar, is more potent and can be given in oral form as a primary therapy. In January 2015, Naurex reported on an intermediate-stage trial of NRX-1074 in intravenous form, given in doses of 1, 5, and 10 milligrams against a placebo. Tests of the drug as an oral therapy are planned for later.

The results show patients receiving the highest (10 milligram) dose of NRX-1074 had ratings on the standard Hamilton scale 14 points lower than patients receiving the placebo, as soon as 1 day following treatment. According to Naurex, the effect size of the antidepression efficacy — a quantitative measure of strength of a statistical relationship — after 24 hours is more than twice the effect size reported for other antidepression drugs taken in multiple doses over 4 to 6 weeks. In addition, 72 percent of patients receiving the highest NRX-1074 dose reported a reduction of half or more in Hamilton scale scores after 24 hours, compared to 39 percent for patients receiving the placebo.

The agreement gives Allergan ownership of Naurex’s two clinical stage products, but the technology platform designing therapies that stimulate NMDA receptors and Naurex’s preclinical research will be spun-off to a separate, as yet unamed, company. Allergan, however, will collaborate with the new enterprise on discovery of therapy candidates for  psychiatric and neurological disorders, and will have first rights to license these candidates from that company.

Under the deal, Allergan is paying Naurex’s shareholders $460 million immediately, and another $100 million by January 2016. Allergan, in Dublin, Ireland, says it is focusing on development of new branded drugs, and also announced yesterday the sale of its generic drug business to Israeli manufacturer Teva Pharmaceutical Industries for $40.5 billion. Earlier this month, Allergan licensed from drug maker Merck therapies for treatment and prevention of migraines for $250 million, plus milestone and royalty payments.

Naurex was founded by Northwestern University biomedical engineering professor Joseph Moskal, who is also the company’s chief scientist. At Northwestern, Moskal is director of the university’s Falk Center for Molecular Therapeutics that calls itself a “new organizational model … to translate discoveries with therapeutic potential into clinically useful compounds.”

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Hat tip: FirstWord Pharma

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A Turbulent Two Days

Kayaker in rapids

(A. Kotok)

25 July 2015. If you tried accessing Science & Enterprise on Thursday and Friday this week, 23-24 July, you likely encountered periods when the site was not available. Please accept our sincerest apologies for the outages.

On Thursday, we ran into problems trying to update the site to the latest vesion of WordPress, the underlying blogging engine, where first our logo at the top of the page disappeared, and then the whole site. Thanks to some good work by our hosting service, Hosting Matters, we got the site restored. Let me say that Hosting Matters knows the meaning of customer service; I highly recommend them.

Our apologies also for the duplicate posting of our story on Thursday about cancer drug prices, that may show up twice in RSS feeds and e-mail alerts. We had to reconstruct and repost the story after we restored the site. Our thanks go as well to the ACI Scholarly Blog Index that archives Science & Enterprise, where we could retrieve the text.

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