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First Trial of Alzheimer’s Drug Underway

Brain illustration


17 October 2017. The first clinical trial is underway of a therapy for stopping the progression of Alzheimer’s disease that purports to rebuild neural connections in the brain. The trial, sponsored by M3 Biotechnology Inc. in Seattle, is testing in humans for the first time its small-molecule drug code-named NDX-1017.

Alzheimer’s disease is a progressive neurodegenerative disease affecting growing numbers of older people worldwide. People with Alzheimer’s disease often have deposits of abnormal substances in spaces between brain cells, known as amyloid-beta peptides, as well as misfolded tangles of proteins inside brain cells known as tau. The Alzheimer’s Association says some 5.4 million individuals in the U.S. have the disorder, of which 5.2 million are age 65 or older. By 2050 that number is expected to increase to 16 million.

M3 Bio says NDX-1017 addresses receptors of proteins known as hepatocyte growth factors that stimulate growth of cells and tissue in several organs in the body. Among the functions provided by hepatocyte growth factors are self-repair of injured organs and protection against inflammation. In the case of NDX-1017, these properties are directed to the repair and protection of neurons, or nerve cells, in the brain.

The early-stage clinical trial is enrolling 92 individuals to test NDX-1017’s safety, tolerability, and chemical activity in the body. NDX-1017, given as injections under the skin, will be tested against a placebo among younger healthy adults, age 18 to 45, and older healthy individuals, age 60 to 75. The research team is testing single and multiple doses of the treatments at ascending levels, looking primarily for signs of adverse effects for up to 20 days. However, the team is also assessing concentrations of NDX-1017 in blood plasma over 48 hours and the length of time the drug remains in the blood.

M3 Bio began in 2013, while company co-founder and CEO Leen Kawas was a postdoctoral research associate in pharmacology and toxicology at Washington State University in Pullman. The company’s R&D is supported by grants from Alzheimer’s Drug Discovery Foundation and Dolby Family Ventures, as well as $12 million in equity raised in the company’s first venture funding round, according to the Seattle Times. Alzheimer’s Drug Discovery Foundation and Dolby Family Ventures, along with the W-Fund that supports tech start-ups in Washington State are also funding the clinical trial.

“Current drugs on the market for Alzheimer’s patients offer only symptomatic relief,” says Kawas in a company statement, “whereas we anticipate NDX-1017 will slow, halt and potentially restore lost function. The preclinical studies suggest we are on the right path, and we are excited to advance a much-needed brain regenerative therapy to alleviate the suffering of millions afflicted by the disease, and their families, around the world.”

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Univ. Spin-Off Reports Cancer Immunotherapy Advance

For-Robin lab

Kate Rittenhouse-Olson, left, with company scientist Diala Ghazal. (Douglas Levere, University at Buffalo)

17 October 2017. A highly targeted synthetic antibody, developed by a university spin-off enterprise, was shown to destroy human breast cancer cells grafted in lab mice. The findings reported by the company For-Robin Inc. in Williamsville, New York, appear in the September 2017 issue of the journal Neoplasia. For-Robin founder and president Kate Rittenhouse-Olson plans to discuss the findings next week at the BioNetwork Partnering Summit in Laguna Niguel, California.

For-Robin is developing immunotherapy treatments for breast cancer that address the Thomsen-Friedenreich glycoantigen, absent or masked by carbohydrates in normal tissue, but present in several human cancers, including breast, colon, bladder, and prostate. The company licensed research by Rittenhouse-Olson, then a University at Buffalo microbiologist, that led to creation of an antibody called JAA-F11, designed to bind on and stop the growth of human cancer cells with Thomsen-Friedenreich antigens on their surface.

In the paper, the researchers tested a humanized form of JAA-F11 antibody, engineered to prevent rejection by the immune system, in lab cultures and mice. The results show in lab cultures the humanized antibody kills cells from both breast and lung cancer tumors. In mice grafted with human breast tumors, the antibody stopped the growth of these tumors, both working alone and combined with maytansine, a cancer-killing compound. The authors report the antibody also prevented tumor cells from binding with blood vessel cells to help prevent spread of the cancer, and non-cancerous cells were unaffected by the treatments.

The researchers believe the JAA-F11 antibody both alone and configured as an antibody drug conjugate, designed to more precisely deliver chemotherapy drugs to reduce adverse effects of conventional chemotherapy, can treat multiple types of breast cancer. Among these variations is triple-negative breast cancer that expresses no estrogen, progesterone, or HER2 receptors used as targets for other breast cancer treatments.

Rittenhouse-Olson recently left her professorship in microbiology to devote full time to For-Robin Inc. The company is more than a commercial venture to Rittenhouse-Olson. The enterprise is named for her sister Robin that died of breast cancer at age 31. As reported by Science & Enterprise in May 2015, the company received a $2 million Small Business Technology Transfer grant from National Cancer Institute for preclinical development of the JAA-F11 antibody.

“What we are focused on now,” says Rittenhouse-Olson in a university statement, “is fundraising and preparing for human clinical trials, which will include scaling up production of our antibody under controlled conditions that meet the requirements of the U.S. Food and Drug Administration.”

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Online Game Harnessed to Combat Foodborne Toxins

Maize with aflatoxin

Maize with aflatoxin molds (National Institute of Environmental Health Sciences)

16 October 2017. A consortium of companies and university labs is recruiting participants in an online computer game to design synthetic proteins to neutralize a toxin that contaminates food crops. The project aims to design a protein that degrades aflatoxins, a naturally occurring poison that affects food stocks, particularly in the developing world, and known to cause liver cancer.

Aflatoxins are molds produced by fungi, which are generally eliminated early in the supply chain by regulatory authorities in the developed world, but in limited resource areas can poison food stocks, including basic staples like maize and nuts. The molds are highly toxic to animals and humans, and as a result can be passed along to humans by livestock eating contaminated feed. University of California in Davis, one of the participants in the initiative, cites data that show aflatoxins cause some 90,000 cases of liver cancer a year, along with stunted growth and immune system disorders.

The initiative is recruiting participants in FoldIt, an online protein folding game, to design a synthetic protein that best degrades and neutralizes aflatoxins. FoldIt is a game platform where individuals compete to assemble amino acid building blocks into complex proteins. Participants design their amino acid assemblies into chains, with folds in the chains made to achieve specific shapes that in turn achieve specific purposes. FoldIt games are sometimes used, as in this case, to crowdsource solutions for protein folding problems, with imagination and problem-solving ability as important as scientific knowledge to craft a solution.

In addition to UC-Davis, participants in the project include Northeastern University in Boston and University of Washington in Seattle that developed the FoldIt platform. Also taking part are the Partnership for Aflatoxin Control in Africa, food products company Mars Inc., and life science devices and products company Thermo Fisher Scientific.

Participants in the FoldIt game will be given an enzyme with the potential to neutralize aflatoxins by degrading a key protein structure called a lactone ring. In its current state, however, the enzyme is ineffective. FoldIt participants are asked to restructure the enzyme to interact with aflatoxin molecules to degrade the lactone ring, and thus reduce the molecules’ toxicity.

“While aflatoxin has been a known issue for decades,” says UC-Davis biochemist Justin Siegel in a university statement, “advances in computation and biotechnology, coupled with the imagination of players from around the world, may finally result in a solution to this pressing problem.” Siegel adds that, “No single organization can tackle a problem this large, but the uncommon collaboration between the groups coming together here will enable us to not only discover a potential solution, but translate it in a way that has real impact.”

The first round of the Aflatoxin Challenge is now underway, with feedback provided as the puzzles become more complex. Siegel’s lab, supported by Mars Inc. will review the entries to find the most promising designs. Thermo Fisher Scientific is providing its gene synthesis services to encode the top designs. All FoldIt player designs will be available in the public domain, and will not be submitted for intellectual property protection.

Siegel tells more about the initiative in this audio interview with Scientific American.

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Roche, Biotech to Discover New Antibiotics

Klebsiella pneumonia bacteria

Klebsiella pneumonia bacteria (

16 October 2017. A biotechnology company that discovers new drugs through detailed genomic analysis is partnering with drug maker Roche to find new treatments for bacterial infections that resist current antibiotics. The collaboration with Roche is expected to bring Warp Drive Bio in Cambridge, Massachusetts as much as $387 million over the course of the agreement.

Warp Drive Bio is a five year-old company discovering new drugs that address disease-causing proteins considered too difficult to treat with conventional small-molecule drugs or biologic therapies alone. These protein targets, says the company, are either inside cells making them inaccessible to biologics, or do not have particular features needed to bind with small molecule drugs.

Among Warp Drive Bio’s tools is a technique it calls genome mining that searches for molecular targets inside microbes hidden to conventional lab analytical methods. The company says it compiled a database of 4 million gene clusters derived from 135,000 microbial strains, queried by its own search engine to reveal targets expressed by these genomic signatures. These new targets, says the company, make it possible to develop synthetic molecules with new mechanisms for attacking bacteria. Warp Drive Bio says it is evaluating more than 100 previously undiscovered classes of antibiotic candidates not yet analyzed for their potential impact on human health.

Roche identifies new treatments for antibiotic resistance as one of its core research objectives. The agreement gives Roche an exclusive, worldwide license to develop and commercialize undisclosed classes of new antibiotics identified by Warp Drive Bio through its genomic mining techniques. The collaboration is specifically going after gram-negative drug-resistant bacteria. “Gram” refers to a classification for bacteria where the microbes either retain (gram-positive) or shed (gram-negative) a test stain on their protective cell coatings.

Centers for Disease Control and Prevention says each year some 2 million people in the U.S. develop infections resistant to antibiotics, resulting in at least 23,000 deaths. Gram-negative bacteria are resistant to multiple drugs and are increasingly resistant to most available antibiotics, says CDC. These bacteria have built-in abilities to find new ways to be resistant and can pass along genetic materials that allow other bacteria to become drug-resistant as well. Gram-negative infections include those caused by Klebsiella, Acinetobacter, Pseudomonas aeruginosa, and E. coli bacteria.

Warp Drive Bio is receiving an initial payment of $87 million covering option fees and preclinical research. The company is also eligible for up to $300 million in future development, regulatory, and sales milestones of products that result from the collaboration, as well as royalties on sales of those products. Warp Drive Bio, however, will retain the rights to other classes of antibiotics discovered in the project, but not developed by Roche.

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Flashback: Drug Pricing Reform Even Big Pharma Might Like

Science & Enterprise is taking a break From 2 to 13 October. Until then, we will re-run some of our recent special reports. Our regular posts will return on 16 October.

Pills and dollar bill


2 May 2016. At a press event in Washington, D.C. last week, Representative Lloyd Doggett of Texas, a champion of lower prescription drug prices, took aim at drug companies and their business practices. “An unaffordable drug is 100 percent ineffective,” Doggett told an audience at Center for American Progress on 26 April. He noted that 9 out of 10 drug makers spend more on marketing than R&D, with Americans spending 12 times more on drugs than people in Ireland, where some American drug companies are trying to escape for lower corporate tax rates.

Doggett, a senior Democrat on the House Ways and Means Committee, was keynote speaker at a panel discussion of a report from Center for American Progress, a progressive think tank in Washington, D.C. Like Doggett, CAP’s report — titled Enough is Enough — called for action by Congress and the executive branch to bring more transparency to drug pricing, and to create pricing models based more on value to the patient than maximizing revenues to the drug companies. The federal government, said CAP’s report and a panel of experts to discuss its findings, can play a larger role in bringing down drug prices, from exercising its buying power through Medicare and Medicaid, as well as leveraging its support for basic life sciences research.

The pharmaceutical industry in the U.S. has a long track record of successfully heading off actions by governments, either by cutting advantageous deals or through lobbying. But calls for doing something meaningful about escalating drug prices are getting louder and angrier, with the industry now left largely alone to fight its legislative battles. And new technologies could make the industries current economic model as outmoded as Life magazine and the Sears catalog.

High prices causing unfilled prescriptions

The panel, chaired by Ezekiel Emanuel, vice-provost at University of Pennsylvania and long-time proponent of health care reform, included Marilyn Tavenner, CEO of America’s Health Insurance Plans, Debra Whitman, chief public policy officer at AARP, and Joshua Ofman, vice-president for for global value, access, and policy at biopharmaceutical company Amgen. Tavenner joined the health insurance industry group in July 2015 after serving in 2013-14 as Administrator of Centers for Medicare and Medicaid Services, in the U.S. Department of Health and Human Services.

The entire panel, including Amgen’s Ofman, the sole industry representative, agreed high drug prices were a problem and cause for concern. Whitman cited recent surveys by AARP of Americans age 50 and over showing more and more difficulty paying for prescription drugs, including 1 in 3 respondents who did not fill a prescription mainly because of its cost. In addition, three-quarters (76%) of American seniors want government to do more to bring down drug prices, about the same percentage of Americans overall cited in CAP’s report that say drug prices are too high.

The panel discussed several proposals in the CAP report and elsewhere to bring more transparency to drug prices, employ comparative effectiveness research to assess the relative value of different treatments, encourage bulk-sale negotiations with government and large insurers, apply success-based outcome models to justify higher prices for drugs, and limit out-of-pocket cost-sharing in health insurance plans. Other ideas included limits on patent lifetimes and bans on pay-for-delay schemes where drug companies pay makers of generic drugs to delay issuing substitutes with lower prices.

Liberal policy wonks at think tanks aren’t the only people pushing these proposals. Many of these same ideas were expressed in an article signed by 118 cancer specialists in July 2015 in the journal Mayo Clinic Proceedings, and in March 2016 by the American College of Physicians in an article in Annals in Internal Medicine. These statements suggest large segments of the physician community aren’t buying the industry’s arguments.

Amgen’s Ofman pushed back on many of these proposals, noting that the costs for developing new drugs are high because the nature of disease is difficult and complex, with Amgen itself spending $4 billion a year on R&D. Thus measuring the value of drugs is also difficult and complex, particularly when bringing in the needs of special populations, like the disabled or children. Applying a single value formula to drug prices, said Ofman, becomes in effect a cost-control, which would have serious market repercussions.

In addition, Ofman pointed out negotiations by insurance plans can bring down costs for some customers, but hospitals still charge full price for non-insured patients. Moreover, Ofman argued, value should be calculated over the drug’s lifetime, including its generic period. Ofman’s arguments resulted in the other panel members accepting, at least in principle, that the issue does not lend itself to easy answers.

Continue reading Flashback: Drug Pricing Reform Even Big Pharma Might Like

Taking a Break

Airliner taking off

(Matthew Grapengieser, Flickr)

2 October 2017. Science & Enterprise is taking a two-week break. During this time, we will repost stories with our special reporting in recent months. Our regular reporting will resume on Monday, 16 October.

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Infographic – Europe’s High Value Tech Companies

Infographic: Europe's Tech Giants | Statista You will find more statistics at Statista

30 September 2017. We report frequently on equity investments in the technology industry, particularly in the U.S. and Europe. Our friends at Statista this week collected the top European technology companies in market value, displayed in this chart. The U.K. leads all European countries with nearly $US 50 billion in high-value tech companies, according to industry research company GP.Bullhound.

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Gas-Jet Printing Process Developed for Medications

Gas-jet printing

Siddharth Suresh Borsadia prints fluorescein crystals with gas-jet printing. (Levi Hutmacher, University of Michigan)

29 September 2017. A team of material scientists and biomedical engineers designed techniques for producing pharmaceuticals on demand by printing drugs as thin films. Researchers from University of Michigan in Ann Arbor describe their process in the 27 September issue of the journal Nature Communications.

The team led by Michigan materials scientist Max Shtein is seeking better methods for producing medications in safe doses, and with delivery methods best suited for the patients. Shtein and colleagues are also seeking techniques to make drugs that dissolve easier than conventional drugs, which could make available more medications now rejected for low solubility when given as pills or capsules.

The researchers adapted a technique from semiconductor fabrication called organic vapor jet printing for printing fine circuits on computer chips. In this case, the drug’s active ingredients are reduced to nanoscale crystals, combined with an inert gas, such as nitrogen, to carry the particles through a jet printer to the target surface. The surface receiving the jet is cooled so the gas dissipates, leaving behind a film of the condensed drug ingredients. The process allows for adjusting the size and shape of the deposited drug films, making possible a wide variety of dosage quantities, for printing on any number of delivery media.

The researchers tested the process with several organic compounds and current drugs, including the common fluorescing reagent fluorescein, caffeine, pain killer ibuprofen, pain and fever drug paracetamol, the cancer drug tamoxifen, and inflammation and cancer compound BAY 11-7082. These compounds were printed on a variety of media, such as glass lab slides, Tegaterm medical dressings, Listerine tabs, and stainless steel microneedles used in drug-delivery patches. In lab tests, the results show the printed drug films exhibited the same chemical activity as the compounds formulated as powders.

The Michigan team separately tested the printed cancer drugs tamoxifen and BAY 11-7082 against their original forms. In these tests, the researchers found the printed drugs destroyed cancer cells in lab cultures similarly to the medications mixed with the organic solvent dimethyl sulfoxide, a common ingredient in drugs to enable absorption in the body.

The gas-jet technique could also produce personalized drug combinations for patients, rather than prescribing multiple drugs. “A doctor or pharmacist can choose any number of medications, which the machine would combine into a single dose,” says Shtein in a university statement. “The machine could be sitting in the back of the pharmacy or even in a clinic.”

The first users of gas-jet printing, however, may be pharmaceutical companies themselves. The authors foresee drug makers using the methods to speed up drug testing, as well as incorporating the process into continuous manufacturing techniques. Members of the team plan to collaborate with experts in drug design and manufacturing to scale-up the process for continuous manufacturing.

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IBM, UC San Diego Partner on Healthy Aging

Hands of older person

(Steve Buissinne, Pixabay)

28 September 2017. IBM and University of California at San Diego are launching a joint research project to gain new insights with artificial intelligence on cognitive and gut microbe health in older people. Financial and intellectual property aspects of the collaboration between IBM Research and UC San Diego were not disclosed.

The agreement calls for establishing an Artificial Intelligence for Healthy Living Center on the UC San Diego campus in La Jolla. At the center, research teams are expected to investigate cognitive decline among older individuals, but also the role of the human microbiome in the aging process.

The goal of the project is to better understand the key factors that contribute to healthy aging and independent living with a higher quality of life. Over the 5-year lifetime of the project, researchers plan to study the interaction of genetics, environmental factors, daily habits, and the human microbiome on the cognition of older adults.

The microbiome — the complex aggregate community of diverse microbes in humans associated with a wide range of health conditions — is an emerging research field, where disruptions in gut, skin, or mouth microbial communities are increasingly associated with many chronic and degenerative diseases. Among the disorders associated with microbial disruptions is Parkinson’s disease, but because of the complex relationships among these factors, the connections are not well understood.

IBM’s role in the partnership will provide expertise in artificial intelligence, resulting in analytical machine-learning algorithms to find underlying patterns in large-scale databases that identify ways to prevent cognitive decline, not just treat the condition after it occurs. “We want caring for the older population to be not just palliative, but preventive,” says UC San Diego chancellor Pradeep Khosla in a blog post on the IBM web site. “Rather than treating serious cognitive decline, we seek ways to stop it.”

In addition to IBM Research, the initiative is expected to involve UC San Diego’s medical and engineering schools, supercomputer center, and Center for Microbiome Innovation, where IBM will become a corporate sponsor. While funding levels were not disclosed, the project is expected to support 15 UC San Diego faculty members, as well as 46 postdoctoral researchers, students, and research staff.

The partnership with UC San Diego is part of IBM’s Cognitive Horizons Network, where IBM scientists collaborate with colleagues in academic labs to apply artificial intelligence, machine learning, natural language processing and related technologies to advanced research. Earlier in September, Science & Enterprise reported on the opening of a new research lab at MIT, where IBM and university scientists are investigating algorithms to expand machine learning and reasoning, the physics behind artificial intelligence, as well as industrial applications and economic implications of artificial intelligence.

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Disclosure: The author owns shares in IBM.

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Origami Robotics Designed for Fragile Objects

Kiju Lee

Kiju Lee, with Twister robotics device (Russell Lee, Case Western Reserve University)

28 September 2017. An engineering lab at Case Western Reserve University developed a soft robotic arm that grips and manipulates fragile objects, such as in surgery. Researchers led by mechanical and aerospace engineering professor Kiju Lee described their device in a paper presented yesterday at the International Conference on Intelligent Robots and Systems in Vancouver, British Columbia.

Lee and colleagues designed the robotics arm they call Twister, short for twisted tower robot, to offer a highly compact device that can expand, bend, and manipulate fragile objects. Robotics with these features could meet various needs in manufacturing, space exploration, and medicine, particularly in minimally invasive surgery. The team from the university’s Distributed Intelligence and Robotics Lab in Cleveland based its work on origami, a Japanese art form that creates elegant designs folded from single sheets of paper.

The researchers designed Twister as a series of shapes — triangles, hexagons, and octagons — built into a tube, inspired by the work of artist Mihoko Tachibana, who built an origami tower in multiple modular segments. While the team used paper for earlier origami-based robotics, the researchers found constructing a detailed and complex device like Twister would require 3-D printing, following a computer-assisted design.

The device itself uses two types of materials, rigid materials for the surfaces and soft flexible materials for the hinges and splines connecting the modules. The team printed Twister on a Stratasys Connex3 printer, using transparent VeroClear filaments for the surfaces and TangoBlackPlus for the flexible components. Printing the device took about 8.5 hours, with another 8 hours needed for cleaning off excess materials. The researchers estimate hand-folding paper for the device would require up to 20 hours of tedious labor.

The team’s Twister prototype with 10 modules is 62.5 millimeters (2.5 inches) long when compressed, but extends to 255.5 millimeters (10.0 inches). Plastic filament cables connect the modules, with motor-driven pulleys. The researchers fitted Twister with a simple gripper at the end, along with a gyroscope sensor and miniature camera. The system uses an Arduino microcontroller for the motors and a Raspberry Pi controller for the camera.

The researchers tested Twister on two different objects, a cubic block and egg shell. The team ran 40 trials with the arm finding and grasping each object, bending and twisting in different directions, then returning the object to its original spot. The results show a 95 percent success rate with the egg shell, and 78 percent success with the block. The researchers say the unsuccessful attempts were largely due to the simple gripping device with a limited range of motion.

In addition to minimally-invasive surgery, the researchers foresee their robotic arm used in space exploration and manufacturing. In space, its compact size and collapsible design would let it be stored away, then deployed for tasks requiring precise movements of fragile objects. In manufacturing, Twister could help solve a problem of safety in having robotic devices in close proximity to workers. “Because this robot can be made with soft materials,” says Lee in a university statement, “it could be safe to use on an assembly line right next to people.”

The Twister prototype is demonstrated in this video.

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