NKTR-061 (Inhaled Amikacin) Would Combine a Powerful Antibiotic With Innovative Pulmonary Drug Delivery System

TARRYTOWN, N.Y. and SAN CARLOS, Calif., Aug. 6 /PRNewswire-FirstCall/ — Bayer HealthCare and Nektar Therapeutics announced today that the two companies have agreed to develop and commercialize NKTR-061 (inhaled amikacin). This potentially innovative therapy would utilize Nektar’s proprietary pulmonary technology to deliver a specially-formulated amikacin, an aminoglycoside antibiotic, for inhalation deep into the lung. NKTR-061 is under development for adjunctive treatment of Gram-negative pneumonias that often lead to significant morbidity and mortality.

“This new development agreement reinforces our commitment to fight infectious and respiratory diseases and is a natural fit with Bayer HealthCare’s strategy of developing and marketing specialty pharmaceutical products,” said Dr. Ulrich Kostlin, Member of the Executive Committee of Bayer HealthCare. There is a large, unmet medical need for a new approach to fight Gram-negative pneumonias, particularly in ventilated patients infected with difficult to treat, resistant organisms. Nektar’s pulmonary drug delivery technology offers a very promising approach to address this unmet medical need.

As part of this agreement, Nektar will receive milestone payments of up to $175 million associated with the successful development and commercialization of NKTR-061. This includes an upfront payment of $50 million. Subsequent to the successful clinical and regulatory development of the product, Bayer HealthCare and Nektar have agreed to a co-promotion of the product in the United States and to share profits. For sales outside the United States, Nektar will receive tiered performance royalties up to a maximum of 30%.

Under the terms of the agreement, Bayer HealthCare is responsible for the global clinical development, regulatory strategy, manufacturing and marketing of the product, with Nektar participating in all aspects of decision-making and governance.

“We’re very pleased to be collaborating with Bayer HealthCare, a world leader in anti-infective therapies,” said Howard W. Robin, President and Chief Executive Officer of Nektar Therapeutics. “Utilizing Nektar’s proprietary pulmonary technology to address life-threatening infections, Bayer HealthCare and Nektar are building on the important work we’re doing in the area of pulmonary therapeutics.”

Currently, NKTR-061 is being studied in Phase 2 trials for the adjunctive therapy of ventilated patients with hospital-acquired, Gram-negative pneumonias. These pneumonias are a serious problem afflicting patients even in the world’s most advanced clinical settings and are responsible for a significant number of deaths. Increasingly, multi-drug resistant, Gram-negative bacteria have magnified the problem of hospital-acquired infection. Gram-negative pneumonias are commonly seen in patients receiving immunosuppressive therapy, the elderly, and patients undergoing major surgical procedures, aspiration, long hospital stays and prolonged mechanical ventilation. Current treatment involves the administration of systemic antibiotics, which produces significant toxicities and results in marginal benefit to the patient. Some 20-50 percent of patients intubated and on ventilators who acquire Gram-negative pneumonia will die. NKTR-061 (inhaled amikacin), if approved, would be administered while the patient is on the ventilator and also would allow for ongoing dosing (transition therapy) after the patient no longer requires ventilatory support.

This collaboration is Bayer HealthCare’s second with Nektar. In 2005, Bayer and Nektar agreed to collaborate on the joint development of inhaled ciprofloxacin as a potential dry powder therapy for treating pseudomonal infections in patients suffering from cystic fibrosis.

HHMI, August 10, 2007, Throughout human history, mother’s milk has been regarded as the perfect food. Rich, nutritious and readily available, it is the drink of choice for tens of millions of human infants, not to mention all mammals from mice to whales.

But even mother’s milk can turn toxic if the molecular pathways that govern its production are disrupted, according to a new study by Howard Hughes Medical Institute (HHMI) researchers at The Salk Institute for Biological Studies.

“It’s one of those unexpected observations. It tells you the mother can transmit quite a bit more than nutrition through the milk.”
Ronald M. Evans

Writing in the August 2007 issue of the journal Genes & Development, a group led by HHMI investigator Ronald M. Evans reports that female mice that are deficient in the protein PPAR gamma produce toxic milk. The milk that had been nutritious instead causes inflammation, growth retardation and loss of hair in nursing mouse pups.

“We all think of milk as the ultimate food, the soul food for young animals,” said Evans. “The quality of that milk is also something that is genetically predetermined.”

In essence, the new finding reveals a genetic program for ensuring that mother’s milk is the wonder food it is hailed to be: “We stumbled onto a hidden quality control system. Milk has to be a very clean product. It seems there is a whole process the body uses so that milk is scrubbed and doesn’t have anything toxic in it.”

Evans said the finding was unanticipated, discovered when his group engineered mice to be deficient in PPAR gamma, a protein that helps regulate the body’s sugar and fat stores. Mouse pups developed growth retardation and hair loss when they nursed on mothers who lacked the gene to produce PPAR gamma in blood cells and cells that line the interior of blood and lymph vessels.

“It’s one of those unexpected observations,” Evans explained. “It tells you the mother can transmit quite a bit more than nutrition through the milk.”

Evans’s group found they could reverse the toxic effects of the milk by letting the affected mouse pups nurse on a mother without the genetic variation in PPAR gamma.

Further studies showed that the mouse mothers with the PPAR-gamma deficiency produced milk with oxidized fatty acids, toxic substances that can prompt inflammation.

Evans and his colleagues showed that they could reverse the toxic effects of the milk by administering aspirin or other anti-inflammatory agents. “If you suppress the inflammation, the hair grows back,” said Evans.

PPARs are a widely studied family of nuclear receptors, proteins that are responsible for sensing hormones and other molecules. They work in concert with other proteins to switch genes on or off and are intimately connected to the cellular metabolism of carbohydrates, fats and proteins.

Although their discovery came as a surprise, Evans said it should have been obvious that there would be a mechanism in place to ensure the quality of milk.

“We should have realized there is something very special about it,” he said. “The reason we haven’t heard about toxic milk is because there is a system that keeps it clean. It is logical and should have been anticipated.”

In Evans’s view, PPAR gamma’s role in ensuring the quality of mother’s milk is likely to be a fundamental feature of evolution.

Lactating mothers, he noted, are not protected from inflammation, yet the milk they produce must be a pristine product: “Healthfulness in the body or products of the body is due to a (genetic) program, a process designed over the course of evolutionary history to maintain health.”

PPAR gamma’s role in cleansing milk is “a very straightforward variation on how this system controls both lipid metabolism and inflammation. It’s the secret of keeping them apart. That may be the reason the whole system exists,” Evans said.

In the human population, there are variants in the genetic program that governs PPAR gamma, which alters the fate of sugar and fat in the body. The system is already the target of anti-inflammatory drug therapy used to manage conditions such as diabetes.

Co-authors of the new Genes & Development article include Yihong Wan, Ling-Wa Chong and Chun-Li Zhang, all of The Salk Institute; and Alan Saghatelian and Benjamin F. Cravatt of The Scripps Research Institute.

HHMI

August 05, 2007
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Genetically disabling the sensory organ that mice use to detect pheromones causes female mice to behave like males.

By short-circuiting the sensory organ that detects the chemical cues mice use to attract mates, a team of Howard Hughes Medical Institute (HHMI) researchers has prompted female mice to behave like male mice in the throes of courtship.

The finding, reported August 5, 2007, in the journal Nature, suggests that the neural circuits that govern gender-specific behaviors, such as aggression and courtship, are similar in the male and female brain. According to the new study, the sexual behaviors of female mice, at least, are ruled by a pheromone-detecting organ that engages a neural circuit that determines whether a mouse shows its feminine side or acts like a male.

Biologists have long searched for the root causes of sexually dimorphic behaviors—those that differ between the sexes. The new findings promise to redirect that quest.

“From a developmental standpoint, the finding is very satisfactory,” said Catherine Dulac, an HHMI investigator and Harvard University professor of molecular and cellular biology who led the new study. “It means you only have to build one brain in a species and that the one brain is built, more or less, the same in the male and the female.”

Dulac’s team, composed of first author Tali Kimchi, a postdoctoral fellow, and collaborator Jennings Xu, a Harvard undergraduate student, plumbed the neural depths of sexually dimorphic mouse behavior by engineering females to have functionally deficient vomeronasal organs. Also known as Jacobson’s organ, the vomeronasal organ is a pocket in the nasal cavity of many animals that is packed with receptor cells. It is the key detector of pheromones, chemical signals that elicit specific behavioral responses in certain animals, including mice.

The researchers found that female mice whose vomeronasal organs were genetically disabled behaved like males in the throes of courtship, exhibiting behaviors such as mounting, pelvic thrusts, solicitation and the complex ultrasonic vocalization characteristic of the male mouse. Correspondingly, female traits such as nursing behaviors and maternal aggression were diminished.

The findings provide strong evidence that male sexual behavior is hard wired into the female mouse brain and suggests, more broadly, that male and female courtship behaviors exist in the brains of both sexes and are switched on or off by the chemical cues mice use to initiate sex.

“The female behaves exactly like the male,” said Dulac. “In the big picture, it suggests that the female brain has a perfectly functional male behavioral circuit.”

“People who observe animal behavior have been struck by the fact that the biggest differences in behavior between animals of a given species are gender based,” Dulac explained, but little is known about the underlying differences in the brain that govern the characteristic patterns of gender-based behavior.

Scientists have explored many avenues to explain sexually dimorphic behavior. To try and ferret out its cause, they’ve looked at everything from the influences of hormones such as testosterone to anatomy, positing that there may be a region of the brain that organizes gender-based behavior.

The sensory-controlled neural switch that governs the circuit is most likely different in male and female mice, Dulac noted, but that may be the extent of gender differences in the brain.

The work of Dulac and her colleagues promises to open a new window to the neural mechanisms that underlie gender-based behavior in animals by bringing the senses and an animal’s ability to process what it sees, hears, and smells into the equation.

What occurs in humans and other animals may be quite different, Dulac noted, because the mouse depends largely on pheromones and its sense of smell, while humans and many other animals respond more to visual cues or a combination of sensory cues.

Scientists have been studying the vomeronasal organ for a century and know its role as a detector of pheromones well. While it is known that the organ is wired to the parts of the brain that govern reproductive behavior, its influence on gender-based behaviors was obscured in past studies because the surgical techniques used to ablate the organ flooded the nasal cavity with blood, disabling the olfactory system. To compare results from mice engineered to have a disabled vomeronasal organ, Dulac’s group surgically removed the organ and ensured the nasal cavity was clear and the olfactory system operational.

“When we removed the vomeronasal organ surgically, we found the animal had the same phenotype” as the engineered mice, Dulac explained.

The new insight into the mechanisms that govern sexual behavior in animals gives science a new avenue to explore the molecular and physiological pathways that lead to differences in sexual behavior, according to Dulac. “Now we can really approach things from a mechanistic point of view,” she said. “We can trace signaling events in the brain and see how brain areas controlling sex-specific behaviors are connected to each other.”

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Gold nanoparticles with branching polymers could attack tumors in multiple ways.

By Prachi Patel-Predd

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Nano weapon: A gold nanoparticle enveloped in treelike polymer branches could act as a multipurpose tool for fighting cancer. Researchers can attach folic acid (pink) and fluorescent dye (green) to the nanoparticle to target and image tumors. Tumor cells could be killed with cancer drugs, which are attached to the particle, and with lasers that heat up the gold.
Credit: Xiangyang Shi, University of Michigan

A new class of specially engineered nanoparticles that can target, image, and kill tumor cells could be a potent weapon against cancer. The new nanoengineered system, designed by physician and researcher James Baker and his colleagues at the University of Michigan, contains gold nanoparticles with branching polymers called dendrimers that sprout off the nanoparticle’s surface.

The particles could be used to launch a multiprong attack against tumors. The dendrimer arms can carry a number of different molecules, including molecules that target cancer cells, fluorescent imaging agents, and drugs that slow down or kill the cells. Once enough of the nanoparticles have gathered inside cancer cells, researchers could kill the tumors by using lasers or infrared light to heat up the gold nestled inside the dendrimers. The nanoparticles could thus kill tumors “by combining chemical therapy and physical therapy,” says University of Michigan researcher Xiangyang Shi, who was involved in the work.

In a paper published in the July issue of Small, the researchers demonstrated targeting and imaging cancer cells in a laboratory dish with the new gold-dendrimer hybrid nanoparticles. They hooked four or five folic-acid and fluorescent-dye molecules to each of the dendrimer branches. Then they processed the particles to remove any extra surface charge, which can make the otherwise safe polymers toxic.

Cancer cells have many more folic-acid receptors on their surface than healthy cells do. The folic acid-laden nanoparticles attached to human cancer cells, and the cells swallowed them, along with the folic acid. The particles, which are only three nanometers wide, easily passed through the cell membrane.

Using a microscope, the researchers could see the particles that had accumulated inside the cells because of the dye molecules. The gold in the particle enhanced the contrast enough for the researchers to see that the particles gathered inside the cells in tiny spherical structures called lysosomes. The goal, Baker says, is to make particles that target cancer genes inside cells. “You would bind this material to, let’s say, an oncogene in a cell and knock out the oncogene without harming anything else,” he says.

But first, the researchers will have to show that their material works inside animals. Many other research groups have developed multifunctional nanoparticles to seek out cancer cells and deliver imaging molecules and drugs. Hundreds of different materials are now undergoing tests–gold nanoparticles, silica nanoparticles, polymer shells, and gold-coated glass beads, to name a few. To work in humans, any cancer nanotherapy has to pass three major challenges: the nanoparticles should target only cancer cells; any nanoparticles that do not accumulate inside cells should get eliminated from the body; and the particles should not trigger the body’s immune response.

The first goal–targeting tumors–has not been easy. “Specificity in drug delivery has been historically a very elusive goal,” says Mauro Ferrari, chair of the biomedical-engineering department at the University of Texas Health Science Center, in Houston. Because the new particles have dendrimers on which the researchers can attach different targeting molecules, the technique might work. But the real test will be doing that inside the body. “Targeting cancer cells can be done in a million different ways in the lab,” Ferrari says. “But translating the technique into animals and humans has proven to be very difficult.”

Baker believes that the polymer dendrimers should do the trick. In a 2005 study, his research team showed that dendrimer molecules–without gold inside–that were loaded with folic acid and a cancer drug specifically targeted human tumors in mice, and slowed or killed the tumors more efficiently than the drug alone. The researchers are now testing the new gold-dendrimer hybrid particles in mice and expect the particles to be just as effective as the plain dendrimers.

The small size of the new particles should ensure that they get eliminated from the body. The particles are smaller than most other nanoparticle systems designed for cancer therapy, according to Baker, so they shouldn’t accumulate in vital organs such as the kidney, liver, or lungs. But their small size might raise other safety issues. Inside animals or humans, the nanoparticles could get into other cells, says Raoul Kopelman, a professor at the University of Michigan’s Center for Biological Nanotechnology, who was not involved in the new work. “If you deal with animals or humans, there are many kinds of cells,” Kopelman says. “Will they get into other cells like immune cells? It needs to be tested.”

The most important problem to solve, says Ferrari, is how to make nanoparticles that can stealthily avoid the body’s natural defense mechanisms and get to tumors. “The body has so many booby traps that keep drugs and nanoparticles and everything that is foreign [from getting] into anything of significance in the body,” he says. “If you can build on top of the dendrimer platform the ability to make it across biological barriers with great efficiency, then we have a great breakthrough.”

PresCare is using a Wi-Fi-based RFID system to enable its residents to quickly and easily call for help, and to alert staff if a resident wanders into a dangerous area.
Copyright RFID Journal LLC 2008, Used With Permission

By Beth Bacheldor
RFID Journal Inc., Aug. 8, 2007—PresCare, an Australian provider of elderly care, is using a Wi-Fi-based RFID system to enable residents to quickly and easily call for help when they need it. The medical alerting system notifies caregivers any time a resident wanders into a dangerous area or hasn’t moved for a long time, indicating they might need help.

PresCare operates five facilities and two community centers in Queensland. The company is using active tags and related hardware and software from San Mateo, Calif.-based real-time location system (RTLS) provider AeroScout.

The AeroScout system includes active 2.4 GHz RFID tags; exciters, which activate the tags, causing them to transmit their identification numbers; and the AeroScout Engine, which calculates tag locations by processing data from the tags and various Wi-Fi access points. The system also includes AeroScout’s MobileView software, which can portray location information on a map, in a table or in a report. Surecom, a local company, served as the systems integrator for the implementation.

PresCare began implementing the RTLS in mid-January at its Mount Tamborine site, says Ash Hanna, Surecom’s CEO, and has been running it since the beginning of February. About 100 tags are in use, says Joshua Slobin, AeroScout’s director of marketing. Affixed to lanyards that can be worn around the neck, the tags measure approximately 2 by 1.5 inches and a half-inch thick.

The tags are water-resistant and feature large, easy-to-find call buttons that residents can press when they are in trouble or need assistance. “PresCare wanted an emergency-alerting system that would give their residents full range of motion,” Slobin says. “They can go anywhere in the facility and not have to be necessarily watched over at all times—but if there was an emergency, they could press a button that would send an alert.” PresCare staff also wear the tags so they can easily issue an emergency alert.

When a tag’s call button is pressed, the tag transmits its unique ID number to a nearby Wi-Fi access point, which passes that information on to each staff member’s mobile handheld device, as well as to flat-screen monitors installed throughout the complex. AeroScout Exciters are positioned at doorways, exits and other chokepoints, to detect when residents move through them.

The system can locate the room in which a tag is located, and includes a set of configurable rules designed to trigger alerts when broken. For example, if the system fails to detect a tag’s movement for a specified amount of time, or detects that a resident has wandered into an off-limits or dangerous area, an alert can be issued.

According to Slobin, a caregiver responding to an emergency alert presses the call button on the resident’s tag in a predetermined pattern. This informs everyone involved that the call has been attended to.

So far, Hanna says, nurses and residents are satisfied with the system. Initially, he states, Surecom had set up an audible alert that sounded throughout the facility whenever a call button was pressed, but “we soon took it off, and the residents prefer the peace and quite.”

PresCare has already placed an order to install the system at a second site, Hanna notes, and is looking to implement it at a third site as well, by the middle of next year. When all three systems are up and running, more than 700 tags will be in use for 260 residents and all the staff.