From the category archives:

Drug discovery

Alprolix FDA approval recombinant factor IX rFIXFc hemophilia B coagulation

(Courtesy Biogen Idec)

A few weeks ago Vector brought you the backstory of how a clotting factor for hemophilia was made to last longer in the blood, allowing injections to be pared to once every week or two, rather than two to three per week.

Today we bring more good news: following a successful Phase III trial, rFIXFc recently received the green light for marketing from the FDA and from Health Canada.

Developed by Biogen Idec under the trade name Alprolix™, rFIXFc—a modified version of clotting factor IX—is the fruition of a technology first envisioned by three researchers—gastroenterologists Wayne Lencer, MD, of Boston Children’s Hospital, and Richard Blumberg, MD, of Brigham and Women’s Hospital, and immunologist Neil Simister, DPhil, of Brandeis University—for large protein drugs. Their idea: to extend the drugs’ half-lives by protecting them from being ground up by cells. Full story »

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Group handshake representing a consortiumDavid Altman is manager of marketing and communications in Boston Children’s Hospital’s Technology and Innovation Development Office.

Successful therapeutic development requires multiple stakeholders along the path from discovery to translation to clinical trials to FDA approval to market availability. At various points along this path, academia, industry, government, hospitals, nonprofits and philanthropists may work together. Would bringing these stakeholders together from start to finish lead to greater success?

A growing number of private-public consortia are launching in defined “pre-competitive” spaces where potential rivals collaborate to generate tools and data to accelerate biomedical research. In 1995, consortia were rare in health care: Only one was created. In 2012, 51 new consortia were launched, according to the organization Faster Cures.

Why? you may ask. Banding together in consortia can reduce costs, minimize failures and shorten the timeline to approval for new drugs. Full story »

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Meat grinder protecting protein drugs from being ground up by cells clotting factors

Cells can grind up large protein drugs. A new technology may help those drugs escape and stay in the bloodstream longer.

Getting drugs to stay in the bloodstream longer is a big deal when it comes to treating chronic diseases. You see, a drug’s half-life—the time it takes for half of a given dose to be cleared from the body—determines how long its effect(s) last.

If a drug’s half-life is short—meaning it’s cleared quickly—patients will have to take the drug frequently. Given that someone with a chronic condition could be on the medication for many years—say, patients with severe hemophilia, who endure frequent infusions of clotting factors—a short half-life can translate into high cost. Depending on side effects and how the drug is administered, quality of life may also suffer.

Several years ago, Wayne Lencer, MD, a researcher in Boston Children’s Hospital’s Division of Gastroenterology, Hepatology and Nutrition, and his collaborators Richard Blumberg, MD, at Brigham and Women’s Hospital (BWH) and Neil Simister, DPhil, at Brandeis University came up with a way to make protein-based drugs like clotting factors stay in the circulation longer: by keeping cells from grinding them up.

The first drug based on their work—a form of the factor IX clotting factor—just passed a Phase III clinical trial reported in The New England Journal of Medicine. Full story »

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Did arbaclofen really fail in autism and fragile X?

Did arbaclofen really fail in autism and fragile X?

Walter Kaufmann, MD, is co-director of the Fragile X Syndrome Program and a member of the department of Neurology at Boston Children’s Hospital. He was site principal investigator for three arbaclofen trials sponsored by Seaside Therapeutics and currently advises the company on data analyses. This post is second in a two-part series on clinical trials in autism spectrum disorders. (Read part 1)

The outcomes of drug trials in autism spectrum disorder (ASD) have, to date, been mixed. While atypical neuroleptic drugs have been effective for treating disruptive behavior in people with autism and are FDA-approved for that purpose, no available psychotropic drug has improved the core symptoms of ASD, such as social interaction deficits or stereotypic behaviors.

The heterogeneity—diversity—of ASD in both causes and symptoms may explain treatment failures to some extent. However, we have also lacked drugs targeting the brain mechanisms that underlie ASD. For this reason, targeted trials in fragile X syndrome, informed by neurobiology, have raised hopes of finally addressing core autistic symptoms.

Fragile X syndrome is a genetic disorder in which ASD occurs in 15 to 40 percent of cases. Initial results from a Phase 2 trial using the GABA-B agonist arbaclofen demonstrated relatively selective improvements in social avoidance in a wide age-range sample of subjects. Full story »

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nanomedicineGood things, including therapeutics, can come in small packages—and increasingly this means nano-sized packages. For a sense of the scale of these diminutive tools, a strand of human DNA is 2.5 nanometers in diameter.

Nanomedicine offers the promise of drugs that are activated by physiologic stimuli in the body (like the shear stress of blood flow that’s partially blocked by a clot), that can home to very specific targets in the body (like pancreatic islets that are being attacked by the immune system in diabetes) and that carry their own imaging agents—a built-in “metric” to show that they’re working. Biomaterials are being crafted to enhance their properties—like adding gold “nanowires” to heart patches to increase their electrical conductivity.

Vector’s new sister publication, Innovation Insider, looks at the promise and challenges of nanomedicine—both technical and regulatory. Read more about nanoscissors, theranostics, quantum dots and how the future is nano.

If you’d like to receive Innovation Insider in your inbox, sign up here.

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Using a novel 3-D culture method, scientists were able to prod lung (bronchioalveolar) stem cells to produce colonies containing the cell type of choice: airway (bronchiolar) epithelial cells, alveolar epithelial cells or both. (Images: Joo-Hyeon Lee)

Using a novel 3-D culture method, scientists were able to prod lung (bronchioalveolar) stem cells to produce colonies with the cell type of choice: airway (bronchiolar) epithelial cells, alveolar epithelial cells or both. (Images: Joo-Hyeon Lee)

Someday it may be possible to treat lung diseases like emphysema, pulmonary fibrosis or asthma by prodding the lungs to produce healthy versions of the cells that are damaged.

That’s the hope of researchers Carla Kim, PhD, and Joo-Hyeon Lee, PhD, of the Stem Cell Research Program at Boston Children’s Hospital. In the Jan. 30 issue of Cell, they describe a pathway in the lungs, activated by injury, that directs stem cells to transform into specific kinds of cells—and that can be manipulated to enhance different kinds of repair, at least in a mouse model.

By boosting the pathway, Kim, Lee and colleagues successfully increased production of alveolar epithelial cells, which line the lung’s alveoli—the tiny sacs where gas exchange takes place, and that are irreversibly damaged in diseases like pulmonary fibrosis and emphysema. Full story »

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The footpads of diabetic mice (line-D) treated with a cream containing XIB4035 have increased numbers of nerve terminals (shown in green in the lower right panel), whereas mice given a control cream (lower left) do not. The top two panels represent healthy “wild type” mice.

The footpads of diabetic mice given a cream containing XIB4035 (lower right) have new nerve terminals (shown in green), whereas mice given a control cream (lower left) do not. The top two panels represent healthy “wild type” mice.

About half of people with diabetes develop peripheral neuropathy. The most common form, small-fiber neuropathy, generally starts in the feet, causing pain, odd sensations like pricks and “pins and needles,” and—the most worrisome feature—a loss of sensation that can increase the chance of ulcers and infections.

In some cases, that may lead to the need for amputation—as happened with my diabetic great-grandfather whose numbed feet, unbeknownst to him, got too close to the fire.

While there are some treatments to reduce pain, there’s nothing that restores sensation. Nor do any existing treatments address the underlying cause of the neuropathy: the degeneration or dysfunction of the endings of the sensory neurons in the skin. Full story »

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A zebrafish model of leukemia has helped find that an antipsychotic drug has anticancer properties.One of the hot trends in drug discovery could be called drug re-discovery: finding new uses for drugs that have already received FDA approval for a different indication.

It’s an approach that allows researchers and clinicians to rapidly test potential treatments for rare or difficult-to-treat conditions. Because the drug’s safety profile is already known, much of the preclinical and early clinical work that goes into developing a drug can be bypassed.

It was this kind of strategy that Alejandro Gutierrez, MD, and A. Thomas Look, MD, of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, and Jon Aster, MD, PhD, of Dana-Farber Cancer Institute and Brigham and Women’s Hospital, had in mind when they started screening a library of nearly 5,000 FDA-approved compounds, off-patent drugs and natural products using a zebrafish model of T-cell acute lymphoblastic leukemia (T-ALL).

And with that strategy, they may have struck gold. Just not in the way they had expected. Full story »

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Roulette_wheel2013 saw an accelerated crumbling of borders and boundaries in health care, fueled by technological and scientific advances. Boundaries between high-tech Western medicine and global health practices have begun blurring in interesting ways, as are those between home and hospital, patient and doctor and even a patient’s own body and the treatment used for her disease.

Last year also saw a fierce political fight over the Affordable Care Act (ACA)—aka Obamacare—ending in some six million people crossing the boundary from uninsured to insured, according to HMS, if you count Medicaid and Children’s Health Insurance Program eligibles.

What does all this portend for 2014? This year, Vector asked leaders from all walks of life at Boston Children’s Hospital to weigh in with their predictions. Full story »

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asthmatic airway

Obesity may set off innate immune factors that inflame the lungs.

Both asthma and obesity have surged in recent decades, and a growing body of literature is linking the two conditions. Various explanations have been proposed: One recent study suggests that hormonal factors in obesity may regulate airway diameter; another suggests that obesity activates asthma-related genes.

“Why obesity predisposes a person to asthma has been a real puzzle,” says Dale Umetsu, MD, PhD, who recently researched the problem with Hye Young Kim, PhD, and other colleagues in the Division of Allergy and Immunology at Boston Children’s Hospital. “Our goal was to find the connection between these two problems, which occur in both children and adults, and to explore possible new treatments.”

The team’s research indicates that obesity alters the innate immune system—the body’s first responder to infection—in several ways, resulting in lung inflammation. Published earlier this month in Nature Medicine, their work also suggests a completely new, “druggable” approach to treating patients with obesity-associated asthma, for whom standard asthma drugs often work poorly. Full story »

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