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RNA Flu Therapy Clinical Trials Complete Enrollment

Influenza ultrastructure illustration (Dan Higgins, CDC)

Influenza ultrastructure illustration (Dan Higgins, CDC)

19 February 2015. Two late-stage clinical trials testing an influenza treatment that disrupts a virus’s genetic replication ability finished recruiting more than 2,000 participants worldwide. The trials are being conducted by MediVector Inc., a drug development company in Boston, for Joint Project Manager Medical Countermeasure Systems, an office in the U.S. Department of Defense developing treatments and preventions for chemical and biological warfare agents.

The drug tested in the trials, favipiravir, is an anti-viral compound first developed by Toyama Chemical Co., a unit of Fujifilm in Japan. Favipiravir is taken orally for five days and works by blocking the ability of ribonucleic acid or RNA in the virus to replicate. RNA is genetic material similar to DNA, containing instructions reflecting the DNA code sent to the body’s cells. The compound is designed by Toyama to act against a variety of viruses that replicate through their RNA, and because it targets the virus’s basic replication mechanism, can avoid being neutralized by resistance from mutations.

The two clinical trials test favipiravir against a placebo, among patients with uncomplicated influenza. In each trial, the main objectives are to reduce the amount of time patients experience fever and other symptoms such as cough, sore throat, and headache. The trials are also looking at the drug’s safety, actions of the drugs in the body, and changes in viral load. One trial recruited patients in the U.S., Canada, Mexico, and six countries in Central and South American. The other trial has patients from the U.S., Australia, New Zealand, Russia, South Africa and nine countries in Europe.

Favipiravir was tested in a intermediate stage clinical trial with 530 patients in the U.S. MediVector says the trial shows the drug reduces the time patients suffer flu symptoms compared to a placebo. In addition, says the company, patients taking favipiravir cleared the virus faster than patients receiving the placebo. The drug was also well tolerated with no adverse effects reported during the study.

MediVector is a drug development enterprise making extensive use of software and data-driven decision-support systems that the company says speeds up the process of developing new drugs and taking them to market.

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Synthetic Bone Marrow System Produces Platelets

Alessandra Balduini

Alessandra Balduini (alessandrabalduini.com)

19 February 2015. Bioengineers in the U.S. and Italy designed a programmable bioreactor system that emulates bone marrow to produce platelets, blood cells that coagulate to prevent bleeding. The team led by Tufts University bioengineering professors Alessandra Balduini and David Kaplan published its findings last month in the journal Blood (paid subscription required).

Balduini and Kaplan, with colleagues from Tufts in Medford, Massachusetts and University of Pavia in Italy developed a three-dimensional environment that produces platelets in the lab, but the system can also be programmed to test new therapies for blood-related diseases instead of using animals. Platelets are cells in the blood whose function is to stop bleeding from broken blood vessels.

When platelets in the blood are working properly and at normal levels, they respond to signals of a damaged blood vessel from a protein known as thrombin and accumulate at the site forming a clot, which slows the blood flow. The clot forms by platelets depositing a natural polymer called fibrin at the point of damage, which changes the shape of the platelets and lets them clump together in a clot to staunch the blood flow.

Platelets and other blood cells are produced in marrow, the spongy substance in bones, which the Tufts/Pavia system simulates to produce platelets on demand. The system is made from a porous silk sponge providing a biocompatible environment that acts as a reactor, culturing an individual’s own stem and progenitor cells into bone marrow cells, known as megakaryocytes, as well as the supporting endothelial cells. Inside the silk sponge is a microvascular system made from silk and collagen, with proteins that bind the materials together into tiny tubes.

The Tufts/Pavia team tested the reactor system, which produces millions of platelets, although the output per bone marrow cell is lower than normally made by the body. Nonetheless, platelets produced by the system show they aggregate and clot like normal platelets. The system, say the authors, is scalable that makes it possible to generate larger numbers of platelets as needed, which reduces the need to store platelets for later use.

In addition, the bioreactor can be programmed to alter platelets’ characteristics, such as mechanical properties, binding of signaling proteins, and components. This programming ability enables the system to produce platelets resembling those with different diseases, thus offering a platform to test therapies for platelet-related disorders.

“There are many diseases where platelet production or function is impaired,” says Balduini, who is on the faculty at both Tufts and Pavia, in a Tufts statement. “New insight into the formation of platelets would have a major impact on patients and health care.”

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European Patent Issued for Rare Liver Disease Drug

Illustration of liver

(National Library of Medicine, NIH)

18 February 2015. Synageva BioPharma Corp., a biopharmaceutical company developing therapies for rare diseases, received a European patent on its treatment for lysosomal acid lipase deficiency, an inherited disease causing severe disruptions and injuries to the liver. The European Patent Office issued patent number EP2613798 B1 on 11 February to inventor Anthony Quinn, Synageva’s chief medical officer, and assigned to the company as patent owner.

Lysosomal acid lipase deficiency results from a mutation in the lipase A – lysosomal acid – cholesterol esterase gene, also known as the LIPA gene that produces lysosomal acid lipase, or LAL, an enzyme that breaks down lipids or fats. The broken-down lipids, such as cholesteryl esters and triglycerides, then go to the liver for removal from the body. Because of a mutation in the LIPA gene, people with LAL deficiency do not produce enough effective lysosomal acid lipase that causes lipids to accumulate in the liver tissue, as well as cardiovascular and gastrointestinal organs.

As a result, people with LAL deficiency experience life-threatening enlargement of the liver and spleen, dysfunction and fibrosis in the liver, cirrhosis, and eventually liver failure. Also known as Wolman disease or cholesteryl ester storage disease, LAL deficiency among infants occurs in 1 in 528,000 births, although among people of Jewish-Persian heritage, the rate is 1 in 4,200 births. Among older children and adults, the disease ranges from 1 in 40,000 to 300,000 individuals. Current treatment options for LAL deficiency are limited and involve relieving symptoms, such as drugs for lowering cholesterol.

The patent covers Synageva’s methods for treating LAL deficiency that produce an engineered replacement enzyme, known as sebelipase alfa, for the missing or defective lysosomal acid lipase. The patent describes the biochemistry of the replacement enzyme, as well as its functioning in the body, administration, and dosages. A similar U.S. patent was issued for the technology in March 2014.

Synageva, based in Lexington, Massachusetts, intends to market sebelipase alfa under the brand name Kanuma, which received orphan drug designation from U.S., European, and Japanese regulators. The U.S. Food and Drug Administration also granted Kanuma fast track and breakthrough therapy status, to speed review of the drug through the agency.

In June 2014, the company reported results of a late-stage clinical trial among 66 patients with LAL deficiency, where Kanuma met its primary objective of normalizing patient scores on a key indicator of liver injury, compared to patients receiving a placebo. The results also show patients receiving Kanuma improved on other liver conditions related to the disease. Another clinical trial is recruiting participants to test the drug among a broader cross-section of people with LAL deficiency.

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Flu Vaccine Shown to Protect Against Avian Influenza

H7N9 virus

H7N9 virus (U.S. Centers for Disease Control and Prevention)

18 February 2015. Researchers at University of Chicago and Mount Sinai medical centers found people who receive the seasonal flu vaccine also generate antibodies that in lab cultures and animals act against avian (H7N9) and other influenza strains. The team led by Chicago’s Patrick Wilson and Mount Sinai’s Florian Krammer published its findings yesterday in the Journal of Clinical Investigation.

Public health authorities first spotted the human H7N9 virus in China in March 2013, which were believed to first infect poultry and later spread to humans in contaminated environments. Most patients infected with H7N9 experienced severe respiratory illness, with deaths occurring in about one-third of the cases. However, no cases of person-to-person transmission were found, nor were any cases detected in people or birds in the U.S.

Wilson, Krammer, and colleagues were testing the ability of seasonal vaccines, designed to cover more common flu strains, to also prevent infections from uncommon yet still dangerous forms of the disease. Outbreaks of flu each winter are caused by two types of viruses labelled A and B, with a third (C) type of virus causing a less common and severe form of respiratory illness. The two main types of viruses are collections of sub-types and strains that appear irregularly from one flu season to the next.

Public health authorities worldwide plan each year for producing the composition of next season’s vaccines based on research and surveillance coordinated by World Health Organization. The aim of the annual vaccine is to generate an immune response broad enough to prevent seasonal flu infections, even though the strain of A or B viruses may be different from one year to the next. Among the more common varieties covered by seasonal flu vaccines are H3 strains, part of the A group of viruses.

The Chicago/Mount Sinai team isolated antibodies found in 28 volunteers who received a seasonal flu shot, with 83 antibodies identified from the samples. The vaccine was designed to protect against the common H3N2 flu virus, among other more common A and B strains, but the team found in lab cultures 3 of the 83 antibodies also reacted against H7 viruses — part of the A group — even though they were not among the intended targets. In addition, the 3 antibodies appeared to thoroughly counteract H7N9 viruses.

The researchers then tested the 3 antibodies against H7N9 viruses in lab mice. The team inoculated a set of lab mice with the antibodies, and exposed the inoculated mice and a comparable control group to a lethal dose of H7N9 virus. The inoculated mice survived the exposure, while mice in the control group died.

The Chicago/Mount Sinai researchers also tested the antibodies as a therapy, giving a set of lab mice exposed to H7N9 viruses the 3 antibodies about 24 hours after exposure, with the antibodies succeeding in protecting their recipients. The team tested the antibodies against other H3 and H7 varieties, and found the antibodies could neutralize these other strains as well.

The researchers note the antibodies bind to a part of the virus, known as the stalk region, common to both H3 and H7 strains, with the differences in efficacy against the strain likely due to variations in the way the antibodies bind to the viruses. In addition, the antibodies were shown to have at least some effect on viruses with mutations in the stalk region.

Nonetheless, the low number of effective antibodies against H7 strains — 3 of 83 antibodies found in the volunteers — suggest vaccine developers need to find ways of amplifying their effects to protect against less common flu types. “The challenge is to exploit this response on a larger scale to make vaccines or therapeutics that offer broad protection against influenza strains,” says Wilson in a University of Chicago statement. “For now, it’s clear that seasonal flu vaccination provides defense against more than just common strains. Everyone should be vaccinated.”

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Redesigned Crutch Developer Gains $450K in Early Funds

Partha Unnava and President Obama

Partha Unnava and the Better Walk crutch with President Obama at the White House Maker Faire in June 2014 (Better Walk Inc. and whitehouse.gov)

17 February 2015. A company developing a more comfortable alternative to standard underarm or forearm crutches, secured $450,000 in its first venture funding round. Financing for Better Walk Inc., a spin-off from Georgia Institute of Technology and based in Atlanta, is led by MB Venture Partners, a Memphis-based venture capital firm.

A broken ankle playing basketball provided the inspiration for Partha Unnava to invent a more comfortable crutch. After suffering six weeks of pain and fatigue from walking on traditional crutches, Unnava used his biomedical engineering education to design an alternative. Better Walk crutches have plates supporting the torso and that users can lean on, putting less pressure on armpits or forearms, especially when in a resting position.

Unnava started Better Walk in 2013, while still a biomedical engineering student at Georgia Tech, with fellow engineering students Frankie Swindell and Andrew Varghese. After completing his studies last Spring, Unnava became the company’s full-time CEO. He raised $150,000 in seed funding, and joined the Zero To 510 medical device accelerator program in Memphis. The company since relocated to Atlanta.

Better Walk adapted modern design and management techniques to get the new crutch into development and production. The company uses lean start-up principles to quickly build and evaluate prototypes, combining product development and market testing to accelerate a product to market with less waste. Better Walk also made its early models with 3-D printing that enabled the company to exhibit at trade shows and get feedback from customer prospects at a fraction of the cost of earlier techniques.

The company’s founders were named Georgia Tech’s biomedical engineering outstanding entrepreneurs in 2014. Unnava also took part in the White House Maker Faire in June 2014, and was named to this year’s list of Forbes Magazine’s “30 Under 30.”

“The funding will help us to continue down the path of manufacturing and distributing the Better Walk crutch to patients who need it,” says Unnava in a company statement. The company plans to start limited production of the new crutch this spring, largely for hospitals, and scale-up up production from there.

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Patent Awarded for Neurostimulation Electronics

U.S. Patent and Trademark Office

U.S. Patent and Trademark Office (A. Kotok)

17 February 2015. A U.S. patent on electronic components for switching and pulse generation in neurostimulation devices was awarded earlier this month. The Patent and Trademark Office awarded patent number 8,948,880 on 3 February to Barry Yomtov, founder and chief technologist of AdvaStim Inc. in Beverly, Massachusetts, and assigned to the company.

AdvaStim develops modular components for neurostimulation devices, like those to stimulate the spinal cord to reduce back pain. According to the company, many of today’s spinal cord neurostimulation devices suffer from failure rates as high of 30 percent, requiring a more reliable platform. In addition, says AdvaStim, its modular architecture make it possible for device manufacturers to develop systems to address multiple disorders with the same basic set of components.

While electronic therapy implants, including neurostimulation devices, have been around for decades, newer devices are becoming more and more sophisticated, with microcontrollers for directing multiple stimulation therapies to multiple locations in the body. Adding more functions to these devices requires increasing miniaturization, which even with advanced semiconductor technology, has limitations in the number and type of circuits in an implanted unit.

The patent covers AdvaStim’s switching and pulse-generation technology designed to support a single electrode array connecting multiple input to multiple output circuits. The technology includes an interface for pulse generators to connect to the electrode array, and respond to signals from a control device for producing the stimulative energy. The electrode array, says the patent, can be configured on a flexible substrate and shaped around a cylinder carrier.

“Integrating the pulse generator circuitry with a dense array of electrodes in a single compact lead can improve power efficiency and potentially improve the reliability of an implantable neurostimulator device,” says Yomtov in a company statement. “This technology can also provide neurostimulation therapy developers with enhanced flexibility to position devices where needed within the body and help further the next generation of therapy options.”

The patent is expected to support AdvaStim’s chip architecture that the company says supports multi-channel switching and electrode programming required for advanced neurostimulation devices. AdvaStim also provides embedded controller software for the implanted components.

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Image Analysis Company Raises $800K for New Venture

Omero image viewer

Omero includes an image viewer that allows for annotation (openmicroscopy.org)

16 February 2015. Glencoe Software Inc., a developer of image analysis and management software for research and pharmaceutical applications, raised $800,000 to fund a new venture in digital pathology. Financing for the Seattle company’s venture is provided by TIE Angels Group – Seattle and several other local angel investors.

Glencoe is the commercialization arm of Open Microscopy Environment or Omero, an open-source software and data format for visualization, management, and analysis of biological images from microscopes. Omero provides for a standard client-server architecture for image rendering and analysis, as well as connecting to applications software. The specifications are developed and maintained by a consortium of academic research labs and private companies, mainly in the U.S. and Europe. Omero source code is available under a GNU general public license or commercially through Glencoe Software.

Glencoe, founded in 2005, develops utility applications for Omero, and provides customization and support services for the specifications. The company’s lead product is Bio-Formats, a library of translation routines to convert biological images into some 150 file formats. The formats, says the company, support biological functions and activities such as fluorescence, 3-D cell division including color and time-lapse, and high-content screening.

Digital pathology, according to Digital Pathology Association is “a dynamic, image-based environment that enables the acquisition, management and interpretation of pathology information generated from a digitized glass slide.” In research, says the group, digital pathology is used for high throughput scanning and quantitative analysis of slide images and secure archival of pathology data. In the clinic, digital pathology is found in diagnostics, consultations, decision-making, and medical training.

Glencoe aims to help research and medical labs better manage its collections of pathology images. The company plans to harness Omero to help labs store, catalog, and annotate these images for later analysis or sharing with colleagues. Because Omero is configured to read only the metadata, these operations can be done quickly. The latest version (5.0) of Omero, says the company, supports these functions by enabling storage of images in their original formats, and verification of correct formatting and file integrity.

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Thyroid Cancer Drug Approved by FDA

Thyroid cancer awareness ribbon

(thyca.org)

16 February 2015. The U.S. Food and Drug Administration approved on Friday a drug for differentiated thyroid cancers, where the cancer continues to grow despite treatments with radioactive iodine. The drug, lenvatinib, is marketed by Eisai Inc. in Woodcliffe, New Jersey, under the brand name Lenvima.

The thyroid gland helps the body regulate metabolism, using iodine from the blood to make the needed hormones. Cells in the thyroid also generate hormones for controlling use of calcium in the body. Most cancers of the thyroid are differentiated cancers that look like normal thyroid tissue, even under the microscope, and affect the hormone-producing cells processing iodine. American Cancer Society says more than 62,000 people in the U.S. will develop thyroid cancer this year — with 3 times more women than men getting the disease — resulting in nearly 2,000 deaths.

Lenvima limits the ability of enzymes supporting receptors for proteins that promote development of blood vessels and other cells feeding the growth of thyroid tumors. FDA granted the drug priority review, a program that expedites evaluation of new drugs that show significant improvements in safety or effectiveness. The agency says it completed that review 2 months ahead of schedule.

FDA based its approval in part on results of a late-stage clinical trial of nearly 400 patients with progressive thyroid cancer, despite having earlier received radioactive iodine therapy. Results of the trial appeared last week in New England Journal of Medicine (paid subscription required).

Participants in the trial were randomly assigned 2-to-1 to receive Lenvima or a placebo, taken once a day in 24 milligram doses for 28 days. The study looked primarily at overall survival time of patients, but also effect of the drug on their tumors, as well as safety of the drug.

The findings clearly support the drug’s effectiveness. Patients receiving Lenvima survived for more than 18 months, while those receiving the placebo survived for about 4 months. In addition, about two-thirds (65%) of patients receiving Lenvima experienced a reduction in tumor size, compared to about 2 percent of those receiving the placebo.

But many patients receiving the drug had adverse reactions to it. In the trial, 40 percent or more of patients receiving Lenvima experienced high blood pressure, diarrhea,  fatigue, nausea, and decreased weight and appetite. Of the 261 patients receiving Lenvima, 37 or 14 percent had to discontinue to drug because of adverse reactions, compared to 2 percent receiving the placebo. Also, 6 of 20 deaths of patients receiving Lenvima during the trial were considered to be related to the drug.

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Intrexon Acquires Biopharm Company for $60M

Lactococcus lactis bacteria

Lactococcus lactis bacteria (Joint Genome Institute)

13 February 2015. Intrexon Corp., a biotechnology company in Gaithersburg, Maryland specializing in synthetic biology, is acquiring ActoGeniX, developing biologic therapies from engineered microbes. Under the deal, stockholders of ActoGeniX, based in Ghent, Belgium, are receiving $30 million in cash plus another $30 million in Intrexon stock.

ActoGeniX develops therapies from engineered microbes, particularly Lactococcus lactis bacteria, commonly used to produce yogurt and cheese. The company modifies the organisms to produce therapeutic peptides and proteins that it says are taken orally, produced efficiently, and released in the gastrointestinal tract where the are absorbed into the body from 8 to 48 hours, and with few side effects.

ActoGeniX has two products in clinical trials that Intrexon is acquiring along with the company’s technology. A peptide code-named AG013 is designed to prevent and treat oral mucositis, a complication of chemotherapy causing inflammation of the mucous membranes in the mouth. AG013 is in intermediate and late-stage trials. Another biologic code-named AG014 secretes anti-tumour necrosis factor-alpha antibodies to treat inflammatory bowel disease. ActoGeniX recently completed an early-stage safety study, showing it produces the desired chemical effects in the gastrointestinal system, while being well-tolerated.

In addition, the company has biologics in preclinical development for type 2 diabetes, as well as auto-immune disorders celiac disease and type 1 diabetes. Other preclinical programs are investigating oral allergy treatments and diseases of the microbiome, the collection of microbes inhabiting the body.

Intrexon develops genetically engineered products for the pharmaceutical, food, energy, environmental, and consumer markets. The company operates several technologies derived from computational models and software that assemble DNA-based solutions on a commercial scale. The company’s RheoSwitch Therapeutic System induces expression of one or more genes with a library of ligand activators; ligands are binding and signaling molecules. Intrexon’s Laser-Enabled Analysis and Processing or LEAP provides automated, high-throughput cell imaging with laser-based cell processing.

The company says its Cell Systems Informatics platform permits faster design, testing, and learning of new genetic elements, targets, or pathways. Intrexon maintains a database of genome-scale models, bioinformatics, and computational biology tools that it applies to development of cell metabolism and signaling networks. Models of microbial to mammalian systems are used for drug discovery, development, and validation.

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Devices Assembled to Record Doctor-Patient Interactions

Nadir Weibel

Nadir Weibel (Univ of California, San Diego)

13 February 2015. Computer scientists at University of California in San Diego assembled a collection of audio and video devices into a portable package that records doctors’ consultations with patients when also using electronic health records. The team led by computer science researcher Nadir Weibel that includes members from San Diego university and veterans’ medical centers, published its first report on the package in this month’s issue of the journal Personal and Ubiquitous Computing (paid subscription required).

The package of electronics, called Lab-in-a-Box, has sensors, microphones, and video camera with associated software designed to capture the multiple dimensions in interactions between a doctor during consultations with a patient. Collecting the full richness of these interactions is becoming more important, given the amount of attention needed by doctors in recording information into electronic health records.

“With the heavy demand that current medical records put on the physician, doctors look at the screen instead of looking at their patients,” says Weibel in a university statement. “Important clues such as facial expression, and direct eye-contact between patient and physician are therefore lost.”

Lab-in-a-Box hardware tracks the doctor’s computer activity, speech interactions, visual attention, and body movements. The equipment includes an eye tracker that follows where the doctor is looking, a 360-degree microphone recording audio in the room, a depth camera from a Microsoft Kinect device recording body and head movements, and sensors tracking keyboard strokes, mouse movements, and pop-up menus on the doctor’s computer. The system’s software merges and sequences the different data streams to highlight activities that could indicate distractions from the patient caused by attention to the computer.

Lab-in-a-Box is part of a larger assessment of medical records usability in clinical workflows, funded by the U.S. Agency for Healthcare Research and Quality, and led by UC-San Diego medical professor Zia Agha, the journal paper’s senior author. The package is being field tested at UC-San Diego Medical Center and the San Diego Veterans Affairs Medical Center. The team plans to analyze interactions to uncover systematic differences across various specialties and settings.

The journal article offers an early snapshot of the system at work. Lab-in-a-Box, say the authors, has the potential to uncover valuable insights into the interactions between patient, doctor, and electronic health records, leading to improvements in the design of software to reduce doctors’ distractions from patients during consultations. The system could also provide real-time feedback to doctors on their level of attention to the patient.

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