Monthly Archives: February 2013

Competition intensifies over market for DNA-based prenatal tests

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Prenatal DNA testing has been a fiercely contested market of late. Yet another competitor entered the fray last week when Natera, a startup based in San Carlos, California, announced the 1 March launch date of a commercial test that can detect chromosomal abnormalities in the developing fetus from just a drop of an expectant mother’s blood—and with a sensitivity on par of that of more invasive techniques such as amniocentesis and chorionic villus sampling, both of which carry an elevated risk of miscarriage.

Natera now joins three other California-based firms—Sequenom, Verinata Health (a division of sequencing giant Illumina) and Ariosa Diagnostics—in offering such products for women at high risk of having babies with Down’s syndrome or other chromosomal miscounts known as aneuploidies. With US health insurers, including Aetna and Wellpoint, saying they plan to cover the new tests, the market for DNA-based prenatal screening now provides “a billion dollar opportunity,” according to David Ferreiro, an analyst at Oppenheimer & Co. in Boston.

Between the four new tests, Verinata’s and Sequenom’s currently offer the widest range of screening options, with the ability to identify disorders associated with an extra X or Y sex chromosome, such as Klinefelter’s (XXY) and triple X syndrome. This flexibility is reflected in the cost: Sequenom’s MaterniT21 PLUS carries a list price of $2,762, almost twice as much as Natera’s Panorama, which can detect a missing X chromosome but not other kinds of sex chromosome irregularities.

The tests’ sensitivities vary depending on the chromosome, but all companies claim to be able to identify a fetus with Down’s syndrome, caused by three copies of chromosome 21, more than 99 times out of 100. Detecting extra copies of chromosome 13—a condition known as Patau’s syndrome—is more difficult, and Ariosa’s Harmony test does poorest here, with only 80% sensitivity. But it’s also the cheapest, with a sticker price of just $795 (see chart for the full comparison).

Noninvasive Prenatal Genetic Tests Compared{credit}Nature Medicine{/credit}

For now, the DNA-based tests are only thought to provide a screening tool for select populations, and are not considered definitively diagnostic by clinician groups such as the National Society of Genetic Counselors, who worry about the possibility of erroneous results, the lack of data in low-risk populations and the limited number of aneuploidies tested. Thus, most experts—and many of the companies themselves—still recommend that women whose DNA-based tests come back positive follow up with conventional tests such as amniocentesis. Although the additional testing will still mean invasive procedures for some pregnant women, and their attendant complications, “you are limiting those invasive tests to only the high risk groups,” says Joan Scott, a genetic counselor and executive director of the National Coalition for Health Professional Education in Genetics in Lutherville, Maryland.

Ultimately, “women and their providers [need to be] well informed about the benefits and limitations that are inherent in all these tests,” says Scott. “It’s not a cut and dried decision.”

A version of this story appears in the April 2013 issue of Nature Medicine.

US budget cuts imperil domestic and global biomedical research

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{credit}Shutterstock{/credit}

In the medical world, the term ‘sequestration’ is usually preceded by the word ‘pulmonary’ or ‘splenic’ and is used to describe rare diseases that are the focus of research grants funded by the US National Institutes of Health (NIH). But sequestration has now taken on a new meaning.

On Friday (1 March), a series of sweeping federal budget cuts totaling more than a trillion dollars over the next ten years are scheduled to automatically go into effect unless a legislative bargain is reached—and their impact on biomedical research could be dire, with consequences felt both in the US and abroad.

“We are going to maim our innovation capabilities if you do these abrupt deep cuts at NIH,” former agency director Elias Zerhouni, now head of global R&D at the French drug company Sanofi, told the Washington Post. “It will impact science for generations to come.”

The NIH, already suffering through half-a-decade of stagnant funding, will receive a 5.1% cut across the board—a reduction of $1.5 billion from a total budget of $31 billion. Should this happen, the agency’s operation plan is straightforward: fewer projects will get new funding and existing ones will be supported at lower levels. “Cuts will result in slower progress against our most common diseases, such as Alzheimer’s, cancer, AIDS, diabetes and heart disease,” Francis Collins, the NIH’s current director, said at a press conference addressing sequestration last week.

United for Medical Research, a coalition of universities, biotech companies and research associations, estimates that cuts to the NIH budget could lead to 20,000 fewer jobs and a $3 billion economic impact this fiscal year. Potentially more troubling is the effect of sequestration on new researchers. Lower success rates for NIH grants, which have steadily declined since their peak in the early 2000’s, could stall the careers of young investigators. Even training grants, which fund graduate students at universities, are at risk of being cut, said Collins. “This is not a spigot you turn off and turn back on later. If we lose the talents of this up and coming generation, they’re not coming back,” he said.

Although the NIH is the single largest funding source for biomedical research, other agencies—including the Food and Drug Administration, the Agency for Healthcare Research and Quality, the Department of Defense, the Centers for Disease Control and Prevention, the National Science Foundation, and the Agency for International Development—would all receive sequestration cuts.

Combined, the US agencies are the largest funder of research in the world. Their significant contributions to global health and the potential harm sequestration could cause are highlighted in a report released today by the Global Health Technologies Coalition, a group of nonprofit organizations.

With the development of potential HIV preventatives, improved malaria drugs and other global health products, US government research funding has already saved millions of lives and provided economic benefits around the world. If the research pipeline were to be interrupted now, scientific regression, increased long-term costs and needless deaths would result, the report argues. “There is much to lose by pulling back now,” the authors write.

Anemia drug recalled amid safety concerns in dialysis patients

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Vials of Omontys{credit}Affymax{/credit}

After less than a year on the market, a long-acting anemia drug called Omontys (peginesatide), a once-monthly injection used by people with chronic kidney disease, was recalled over the weekend, after US regulators received 19 reports of severe allergic reactions, including some deaths. Shares of Affymax, the Palo Alto, California–based company behind the product, were down 85% today on the news.

Omontys was approved by the US Food and Drug Administration in March 2012 as an alternative to recombinant versions of the hormone erythropoietin, which signals the bone marrow to make more red blood cells, for individuals undergoing kidney dialysis. A synthetic peptide that activates erythropoietin receptors, Omontys offered several advantages over other erythropoietin-boosting options, including longer-lasting effects that reduced the frequency of injections. By comparison, the next longest lasting erythropoietin replacement drug available in the US, darbepoetin, marketed as Aranesp by California-based Amgen, requires biweekly injections (see ‘New blood-boosting drugs aim to staunch renal anemia’).

In clinical trials, Omontys showed no major safety concerns and was actually thought to shield patients from a rare complication of erythropoietin-based drugs in which antibodies develop that target the body’s endogenous hormones, effectively shutting down all blood cell production and exacerbating the anemia. Whereas neutralizing antibodies occurred in just a little over 1% of patients taking Omontys, it is not really known what caused the allergic reactions that led to the recall. “These adverse reactions were not described in the clinical trials for the dialysis patients, and I do not recollect any such responses reported,” says Jeffrey Berns, a nephrologist at the University of Pennsylvania Perelman School of Medicine in Philadelphia, who was a member of the data and safety monitoring board for Omontys.

Although people who took Omontys need to remain vigilant, Berns doesn’t think the product recall should greatly interrupt their therapy. “Since there are other widely utilized alternatives, this [recall] should not adversely affect the patients who are on dialysis because they will be able to use one of the other available agents,” he says. More disturbing to drug companies, Omontys’ recall may setback the development of other peptide-based analogs, according to Berns. “It should prompt closer scrutiny if other peptide-based agents come to clinical trial.”

Antibody–drug combo approved for fighting breast cancer

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Drug regulators in the US have already approved a handful of treatments for women with HER2-positive breast cancer, an aggressive form of the disease in which a cell surface protein known as human epidermal growth factor receptor type 2, or HER2, is elevated. Although most patients with this type of cancer respond well to at least one of the existing anti-HER2 therapies, some individuals with HER2-positive breast tumors develop drug resistance and remain unresponsive to further treatment. For these women, a new drug combination approved earlier today offers hope.

The therapy—known as trastuzumab–DM1, or T–DM1, and marketed under the brand name Kadcyla by Genentech, a US subsidiary of the Swiss drug giant Roche—is a so-called ‘antibody–drug conjugate’ (ADC) that couples Genentech’s blockbuster antibody Herceptin (trastuzumab) to the cytotoxic agent DM1. In a pivotal 1000-person, phase 3 trial, participants treated with Kadcyla had a median overall survival of 31 months compared to 25 months in women given a tyrosine kinase inhibitor that interrupts HER2 and chemotherapy. Fewer women in the T-DM1 treatment arm also experienced severe side effects, although the newly-approved treatment was found to cause liver toxicity, heart toxicity and severe life-threatening birth defects in some patients.

“Kadcyla is the first ADC to result from Genentech’s 30 years of HER2 pathway research and decade of ADC research,” Dietmar Berger, head of clinical oncology at the company, told Nature Medicine. And it looks like all these years of research have paid off for Genentech: the South San Francisco, California–based firm announced this week that it will be hiring 600 more researchers to continue the work on more than 25 ADCs in the Genentech pipeline, including eight currently in human clinical development.

The idea of linking a toxin to an antibody to target cancer has been around for at least 30 years. However, several factors impeded the success of ADCs in the clinic. For example, in 2000 the US Food and Drug Administration approved the first ADC therapy for the treatment of patients with acute myeloid leukemia. The drug was called gemtuzumab ozogamicin, marketed under the name Mylotarg, and consisted of a humanized monoclonal antibody specific for the receptor protein CD33 conjugated to the cytotoxic drug calicheamicin. However, in June 2010 Myotarg’s manufacturer, New York–based Pfizer, voluntarily withdrew the product from the market after follow-up studies showed that Myotarg treatment did not yield improved survival rates and actually demonstrated worse toxicity than other standards of care. The problem, it turned out, was that the toxic drug did not have a very high specificity and would often dissociate from the antibody in the plasma.

The success of Kadcyla can be attributed to the next generation of technology that provides better linking as well as development of more specific and discriminate cytotoxin drugs, according to Daniel Junius, president and chief executive of Immunogen, a Waltham, Massachusetts–based company and one of Genentech’s partners behind the therapy. “This technology develops a highly potent agent that’s 100- to 1000-times more potent than traditional chemotherapeutics,” he says. As “a highly effective therapy without the toxicity that is so common to many cancer therapies today,” this approval should inspire a whole new generation of ADCs, Junius adds.

Image: Shutterstock

Correction (26 February): An earlier version of this story incorrectly stated that trial participants in the arm treated with Kadcyla had a median overall survival of 40 months compared to 20 months in the arm treated with tyrosine kinase inhibitor and chemotherapy when in fact Kadcyla treated group had a median survival of 31 months compared to 25 months in the other group. Nature Medicine regrets the error, which has been corrected.

Under scrutiny, India’s premier medical research council faces review

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BANGALORE — A high-powered panel set up at the request of India’s Ministry of Finance is reviewing the work of the Indian Council of Medical Research (ICMR), the country’s primary funding and coordinating body for biomedical research, based in New Delhi.

The ICMR has faced criticism that the medical research it supports does not adequately address public health problems. Such critiques, it seems, have prompted the ministry to seek an external audit of the ICMR’s research programs before the government releases the 85 billion rupees ($1.6 billion) that the council has asked for over the next five years—twice as much as it got for the previous five years—including 31.5 billion rupees for new scientific institutes and an upgrade of existing ones.

Prakash Tandon, a neurosurgeon at the government-funded National Brain Research Centre in New Delhi who heads the 11 member committee, told Nature Medicine that a new direction for medical research will be formulated after critical evaluation of the usefulness and public health relevance of programs in each of the ICMR’s 27 institutes. It’s likely that a number of duplicated programs across different ICMR institutes will be recommended for closure, added pathologist Indira Nath, an emeritus professor at the National Institute of Pathology in New Delhi and a committee member. The review of the ICMR began two weeks ago and a report will be submitted within the next two months, according to Tandon.

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Nanoparticles engineered to shuttle cancer drug past immune system

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Protein-bound nanoparticle beads are ingested by macrophages, as seen in the phase contrast (left) and fluorescent microscopy (right) images. Beads in green are ingested, whereas red-yellow beads are still outside.{credit}Richard Tsai, University of Pennsylvania. {/credit}

The body’s first line of defense, known as the innate immune system, protects against foreign invaders, including tiny microbes, bacteria or viruses. Yet it also poses a major challenge for therapeutic applications that rely on microscopic drug-delivering vehicles, or nanoparticles. These nanoparticles are in the same size range as many pathogens and are quickly detected and destroyed by macrophages, the innate immune system’s sentinel cells.

Macrophages rely on proteins in blood serum that stick to foreign objects in the bloodstream; these biological ‘red flags’ attract macrophages to engulf the intruders. In the past, scientists working on nanoparticles have attempted to circumvent this process by, for example, masking the engineered particles with a compound called polyethylene glycol, or PEG, to create a “stealth” coat that blocks these blood proteins from sticking to the nanoparticle surface.

A new approach exploits an Achilles’ heel of the innate immune system. Despite their veracious appetite, macrophages are discriminate consumers because they recognize a specific “don’t eat me” signal on the surface of our own cells, represented by a protein called ‘cluster of differentiation 47’, or CD47. On the basis of this insight, Dennis Discher, a biochemist at the University of Pennsylvania School of Engineering and Applied Science in Philadelphia, and his team devised a new way to get these nanoparticles past the body’s immune defenses. The scientists designed a short peptide sequence derived from CD47 and attached it to nanoparticles to fool macrophages into accepting them as ‘self’ rather than foreign. The details of the technique appear in today’s issue of Science.

“It opens the door for better therapeutic targeting because you suppress clearance by macrophages first and foremost,” says Discher.

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Injectable gel repairs damage after heart attack in pigs

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Processed hydrogel floats in a beaker{credit}UC San Diego Jacobs School of Engineering{/credit}

As you read this sentence, on average at least one person in the US will have started to clutch her chest. The blood flow to her heart will become blocked and cardiac muscle cells will start to die off and get replaced with scar tissue. This person has just suffered a heart attack and most likely will go on to develop heart failure, a weakening of the heart’s ability to pump blood and oxygen. In five years time, there’s a 50/50 chance she’ll be dead.

There are currently no treatments that can repair the damage associated with this so-called ‘myocardial infarction’ (MI), but a potential solution is now showing promise in a large-animal model. Reporting today in Science Translational Medicine, a team of bioengineers at the University of California–San Diego (UCSD) has developed a protein-rich gel that appears to help repair cardiac muscle in a pig model of MI.

The researchers delivered the hydrogel via a catheter directly into the damaged regions of the porcine heart, and showed that the product promoted cellular regeneration and improved cardiac function after a heart attack. Compared to placebo-treated animals, the pigs that received a hydrogel injection displayed a 30% increase in heart volume, a 20% improvement in heart wall movement and a 10% reduction in the amount of scar tissue scar three months out from their heart attacks. “We hope this will be a game-changing technology that can actually prevent heart failure after heart attack,” says UCSD’s Karen Christman, who led the study.

Christman and her team developed their hydrogel by stripping muscle cells from pig hearts, leaving behind a network of proteins that naturally self-assembles into a porous and fibrous scaffold upon injection into heart tissue. They previously tested its safety and efficacy in rats, where they found increased cardiac function and no toxicity or cross-species reactivity.

Similar strategies using naturally-derived scaffolding, such as small intestinal submucosa from pigs in wound patching, are well established. The UCSD study now shows the clinical potential of this approach for cardiac regeneration after a heart attack in a large animal that more approximates humans. Christman has already formed a company based on the technology, called Ventrix, and she hopes to move the product into human safety trials within the year.

Jeffrey Karp, a bioengineer at the Brigham and Women’s Hospital in Boston who is working on a glue that can bind cardiac tissue in live rat and pig hearts (as reported in a news feature this month in Nature Medicine), believes this is promising technology. “Promoting regeneration following myocardial infarction is one of the holy grails in medicine,” he says.

But, Karp warns, “it will be important to validate these results in additional pre-clinical studies, and compare efficacy with other approaches prior to marching onward to the clinic.”

Check out the video for the production process of the hydrogel:

Biotech comes to its ‘antisenses’ after hard-won drug approval

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“With any brand new technology, you never know when the world will be ready for it.” So said Paul Boni, an analyst at Punk, Ziegel & Knoll, in 1998 (as quoted by the New York Times), after the US Food and Drug Administration (FDA) approved its first gene-silencing ‘antisense therapy’, a drug known as Vitravene (fomivirsen), for the treatment of cytomegalovirus infections in individuals with weakened immune systems.

The arrival of Vitravene, a short strand of 21 DNA molecular units that blocks viral replication, was hailed as a major milestone for the biotech industry and was widely anticipated to usher in a new era of antisense products. But no more came. And by the middle of the last decade, Isis Pharmaceuticals, the Carlsbad, California–based company behind Vitravene, ended up pulling the therapy from the market because improvements in other antiretrovirals had effectively eliminated the drug’s target market. Boni’s cautionary words proved all too prescient.

Making antisense of the drug pipeline: Antisense therapies in mid- to late-stage clinical development.

Fifteen years after that first approval, however, antisense technology finally seems ready to make an impact. Late last month, Isis won approval for another antisense drug—Kynamro (mipomirsen), for the treatment of homozygous familial hypercholesterolemia (HoFH), a rare genetic disorder in which the body lack the ability to remove ‘bad’ cholesterol from the bloodstream. The drug is now being marketed by the French giant Sanofi, and several other antisense products are currently in late-stage clinical development.

“This is the end of the beginning for antisense,” says Isis’s chief executive Stanley Crooke. “We feel this is a critical step in the final validation of the technology.”

First developed 35 years ago, the strategy of silencing genes by introducing short antisense stretches of DNA or other nucleic acids that are complementary to an mRNA target has proven useful in laboratory experiments, but translating the technology into the clinic has presented a challenge. For Kynamro, the key was a chemical alteration at both ends of the DNA strand. With this change, the product has an enhanced half-life, stronger affinity for its target RNA and a reduced proinflammatory side effect—all improvements in areas that have previously sunk antisense candidates in clinical testing.

This modification, Crooke says, “is the critical step that we took about 12 years ago, the product of thousands of tiny incremental steps.” Isis currently has 26 candidate antisense drugs in its preclinical and clinical pipeline for treating a range of cardiovascular, metabolic and other types of disorders—the vast majority of which incorporate this chemistry, including an antisense drug that rescued hearing in a mouse model of human deafness, as reported earlier this month in Nature Medicine.

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US report calls for international action in the fight against counterfeit drugs

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Seized counterfeit Viagra {credit}Wikimedia Commons{/credit}

The distribution of counterfeit drugs represents a significant and ever increasing public health concern. Estimated to generate $70 billion in annual sales worldwide, fake or ineffective medications can harm or kill patients, increase legitimate medicine costs, fund criminal activity and even fuel drug-resistance in diseases such as tuberculosis and malaria.

Developing countries are disproportionately affected—researchers reported in The Lancet that more than a third of antimalarial drugs are falsified in sub-Saharan Africa, for example—but no country is immune. As recently as last Tuesday, the US Food and Drug Administration (FDA) issued yet another warning to healthcare providers in the country over batches of counterfeit Avastin (bevacizumab), the blockbuster cancer medication marketed by South San Francisco’s Genentech. This was the third such alert for Avastin in a year.

Although internationally acknowledged as a major public health problem, the fight against counterfeiting has been marred by issues of inconsistent regulatory responses, unclear solutions and even the ambiguity over definition of the term ‘counterfeit’. In response, the US Institute of Medicine, with funding from the FDA, released a report today detailing the scope of the problem and offering recommendations for solutions.

The committee emphasized the need for cooperation between international governments, big pharma companies and civil society groups, such as academia, non-governmental organizations and non-profits—all of which have had contentious relationships of late when it comes to combating counterfeits. (See our April 2010 ‘focus on counterfeit drugs’ for more.)

For example, some member states of the World Health Organization (WHO), including India and Brazil, have accused Western governments of being influenced by major pharmaceutical companies and attempting to use anti-counterfeit measures to stifle unpatented, unregistered or generic drug competition. Versions of these drugs with legitimate formulations represent the only affordable sources of medication in many low-income communities, and some are labeled as counterfeit even if they are neither fake nor ineffective.

“I was shocked in talking with all the stakeholders how deep the suspicion was, and how it caused really a harmful dynamic and lack of cooperation,” committee chair Lawrence Gostin, a global health legal scholar at the Georgetown University Law Center in Washington, DC, told Nature Medicine.

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Mutations that drive early-onset prostate cancer identified, pointing way to specific treatments

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Prostate cancer affects an estimated one in every six males who live past the age of 70, making it the most common type of cancer among men worldwide. The majority of prostate cancer cases occur in men 65 years of age or older, but about 2% of cases occur in those under the age of 50—and these early tumors are particularly aggressive. Until now, scientists didn’t know whether the mechanisms that give rise to prostate cancer in the younger men were different from those in seniors.

New findings, published today in Cancer Cell, show that in young patients prostate cancer develops through a distinct mechanism driven by androgen hormones, such as testosterone. “This brings up the intriguing possibility to develop future screening tests for prostate cancer geared towards young men in which testosterone levels are particularly high,” says molecular biologist Jan Korbel of the European Molecular Biology Laboratory in Heidelberg, Germany.

In an effort to understand the genetic and biological basis of prostate cancer in young men, Korbel and his colleagues sequenced the entire genomes of tumor cells isolated from 11 early-onset prostate cancer patients and compared them to the genomes of tumor cells obtained from seven elderly-onset prostate cancer patients.

The study revealed that the androgen receptors that bind testosterone were much more active in the tumor samples from the younger individuals than the older ones. Further analysis linked this testosterone-driven activation to increased DNA rearrangements that cause cancer, and additional data from more than 10,000 patients confirmed this connection. What’s more, the researchers observed that in the cells from nine out of 11 early-onset patients, testosterone activated androgen receptors that triggered the gene TMPRSS2 to ultimately fuse the gene ERG, promoting cancer. In contrast, the genomic landscape of elderly patients revealed abnormalities that were not linked to the androgen receptors’  activity.

Levi Garraway, a medical oncologist at Harvard’s Dana-Farber Cancer Institute in Boston who was not involved in the current study, thinks that the new link between the genomic landscape of prostate cancer and androgen-driven biology is “encouraging because half of the drugs [approved by the US Food and Drug Administration] for prostate cancer are attacking the androgen axis.” This reinforces that early-onset prostate cancer patients should receive such androgen-targeting drugs as part of first-line treatment. It’s “more bang for the buck,” Garraway says.

“[The] next step in the field should be to first stratify treatments for early and late onset,” Korbel says. Further studies are needed to asses if such tailored screening can lead to greater success in the disease detection, but the observed DNA rearrangement mechanisms in early-onset patients can be a more general phenomena as studies have shown that such rearrangements also lead to chromosomal alternations in breast, ovarian and pancreatic cancers.

 Image: Shutterstock