Monthly Archives: August 2012

Androgen-blocking drug wins US approval for prostate cancer

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Men with advanced prostate cancer now have another treatment option, thanks to the approval today by the US Food and Drug Administration (FDA) of a pill that blocks androgen-receptor signaling and prolongs patient survival.

“To see activity in a post-hormone treated, post-chemotherapy treated prostate cancer population with a drug that doesn’t have myelosuppression [a decrease in blood cell production] and does has a very favorable safety profile is extremely exciting,” says Howard Scher, a prostate cancer specialist at the Memorial Sloan-Kettering Cancer Center in New York. “My patient who got the drug in July 2007 is still on it. I have chills actually. It’s pretty amazing.”

The newly approved agent—Xtandi (enzalutamide), developed by San Francisco’s Medivation and Japan’s Astellas Pharma—works by plugging up the receptors that bind androgens, including testosterone, to prevent those male hormones from fueling the growth of prostate cancer cells. In a phase 3 clinical trial involving around 1,200 men with prostate cancer that had spread despite prior chemo- and hormone-therapy, an international team led by Scher found that participants taking Xtandi lived a median of 18.4 months, compared to 13.6 months for those who received a placebo. The drug also significantly lowered levels of prostate-specific antigen and boosted the time of progression-free survival, with only minimal side effects of fatigue, diarrhea and rare seizures. The results were reported earlier this month in the New England Journal of Medicine.

“This is a very active drug,” says Andrew Armstrong, an oncologist at the Duke Cancer Institute in Durham, North Carolina, who was involved with the trial. “It’s active in the most refractory of patients, and it’s likely even more active in the earlier setting when patients aren’t as far along in their disease process.” Studies evaluating the drug in men with metastatic prostate cancer who have not yet received chemotherapy are ongoing.

According to Decision Resources, the prostate cancer drug market in the US is forecast to more than double over the next decade, increasing from $3.6 billion in 2010 to around $9 billion in 2020. Medivation’s drug is expected to compete most fiercely with Johnson & Johnson’s Zytiga (abiraterone), a pill that inhibits testosterone synthesis. Zytiga won US and European approval in 2011, and earned around $430 million in global sales in the first half of this year, half of which came from the US market.

Like Xtandi, Zytiga is only approved for men who have failed chemotherapy treatment. But this week J&J announced that it had won priority review status from the FDA for the company’s application to get Zytiga approved additionally for prostate cancer patients who have not yet undergone chemo. A decision is expected before the end of the year.

New drug protects memory against stress in mouse study

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A drug previously tested against muscular dystrophy might offer protection against memory problems induced by stressful conditions, according to a preliminary mouse study. Researchers behind the study say the findings could one day contribute to treatments such as post-traumatic stress disorder (PTSD). However other scientists in the field say the mechanism of action is in need of further evidence, and as such the jury remains out on the clinical utility of the agent.

Although people with PTSD can receive help from psychotherapists and antidepressants, drugs to specifically treat the disorder are lacking, as a feature in Nature Medicine detailed. Moreover, doctors know that people who experience shocking violence or abuse and develop PTSD have trouble remembering and learning new things.

In the new experiment, mice were placed each night in a plastic tube without space to move around, creating chronic stress and providing a proxy for PTSD. Andrew Marks, a physiologist at Columbia University in New York, and his team gave half of the animals a daily dose of the drug S107 beginning two days before the stress regime and continuing for the remaining three weeks of research. In their study appearing today in the journal Cell, they report that those mice that received S107 remembered where to find a hidden platform in a water maze a little more than twice as fast as their control counterparts. The treated mice also explored new objects placed in their cages while their stressed-out, untreated counterparts showed less interest.

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Drug pipeline is flush with new options for chronic constipation

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Image: Shutterstock

Felicia Avella has suffered from irritable bowel syndrome (IBS) all her life. Over the years, she has tried numerous drugs to deal with the painful constipation that goes along with her gastrointestinal disorder, but nothing has seemed to provide relief. Then, three-and-a-half years ago, at the age of 61, Avella signed up for a clinical trial testing a new agent called linaclotide, an experimental peptide designed to increase bowel movements in people with chronic constipation. “It just changed my life,” she says. “I didn’t know what normal was until I started on the drug.”

Since the trial ended and the drug was taken away from her, Avella, a retired accountant from Englewood, Florida, has had to rely on an over-the-counter laxative. This drug has helped with her constipation issues, but it hasn’t provided any reprieve from her abdominal discomfort or bloating.

Fortunately for Avella, the US Food and Drug Administration (FDA) today approved linaclotide, which will be marketed as Linzess by Ironwood Pharmaceuticals of Cambridge, Massachusetts, in collaboration with New York’s Forest Laboratories. Avella says she plans to be the first person lined up at her gastroenterologist’s office to discuss switching back to the more targeted agent.

Long-term constipation is a commonly occurring ailment that affects approximately 15% of the US population, resulting in 2.7 million physician visits and 38,000 hospitalizations each year. The first drug ever approved by the FDA for the treatment of chronic idiopathic constipation (CIC) and IBS with constipation was a serotonin receptor activator called tegaserod, which Novartis began selling as Zelnorm in 2002. The Swiss pharma giant pulled the anticonstipation agent five years later, however, after studies linked the drug with an increased risk of heart disease. That has left only lupiprostone, a chloride channel activator marketed as Amitiza by Japan’s Sucampo Pharma and Takeda Pharmaceuticals, for the treatment of lasting bowel problems. Amitiza gained US approval in 2006 and earned $226 million last year in domestic sales alone.

Like lupiprostone, linaclotide works to increase fluid secretion into the gut by stimulating chloride channels in the inner lining of the intestines—which is why both drugs are known as ‘intestinal chloride secretagogues’. Yet, whereas lupiprostone is thought to act primarily on the chloride channel protein 2, linaclotide triggers intestinal chloride secretion through activation of guanylate cyclase type-C (GC-C). This receptor—the same one as that activated by the bacterial toxins responsible for ‘traveler’s diarrhea’—stimulates the release of chloride and bicarbonate, along with water, into the intestinal lumen through the trafficking of messenger molecules that open another chloride channel known as the cystic fibrosis transmembrane conductance regulator. This same pathway has also been shown in rodent models to give the drug distinct pain-relieving properties (Neurogastroenterol. Motil. 22, 312–e84, 2010).

In two phase 3 trials involving a total of 1,276 people with CIC, around 20% of participants who received linaclotide once daily for close to three months showed significant improvements in the frequency of bowel movements, compared to only around 5% of those who received placebo pills (N. Engl. J. Med. 365, 527–536, 2011). Notably, around half the linaclotide-treated patients reported some degree of constipation relief, and a third experienced improvements in bloating and abdominal pain. (Similar response rates were seen in two phase 3 trials involving a combined 1,602 people with IBS with constipation, according to data presented in May at the Digestive Disease Week meeting in San Diego.) The only worrying adverse event found in the published CIC trials was diarrhea, which occurred in around 15% of linaclotide-treated patients compared to only 5% of those on placebo.

“It seems to be very safe, and the side effects are minimal,” says Brian Lacey, a gastroenterologist at the Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire, and a member of the scientific advisory boards for both Ironwood and Takeda. “I’m also impressed by the response rates, keeping in mind that many of these patients who entered the linaclotide studies had likely failed other agents and now responded to something else, which is quite exciting.”

Researchers haven’t tested linaclotide and lupiprostone head to head. Still, on the basis of existing placebo comparisons, analysts say that linaclotide could have a real market advantage. Linaclotide has demonstrated a superior analgesic profile and does not seem to cause nausea—a side effect seen around one in ten people treated with lupiprostone (Aliment. Pharmacol. Ther. 35, 587–599, 2012). With linaclotide, “the data are solid, and everything indicates that a great majority of the patients benefit,” says Juan Sanchez, a pharmaceutical analyst with Ladenburg Thalmann in New York. David Nierengarten of Wedbush Securities in San Francisco estimates that peak US sales of linaclotide will reach $2.4 billion by 2019. “It is eventually going to be a pretty large drug,” he says.

Testing the water

Linaclotide seemed to be the right drug for Felicia Avella. But a chloride channel activator that draws water into the intestines won’t be the solution for everybody. “There will be some patients for whom the problem of constipation is caused by this lack of sufficient fluid in the colon,” says Michael Camilleri, a gastroenterologist at the Mayo Clinic in Rochester, Minnesota, who has led trials investigating many experimental anticonstipation agents, including linaclotide. “On the other hand, there will be some other patients for whom the problem is one of the nerves and muscles not stimulating the propulsion of content through the colon, and there, flushing it from above with water, as it were, might not be sufficient.”

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Heart failure drug piques interest, but not yet winning hearts

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The path to a drug that can reverse heart failure is littered with disappointment. As it stands, a physician can choose to give diuretics, blood pressure drugs or diabetes medication to people who suffer from chronic heart failure but these agents treat only the symptoms, not heart failure itself. Hopes soared in the 1980s when inotropic drugs, which help the heart muscles contract, improved patients’ ability to exercise but were later linked to increased risk of cardiac arrest. Large trials testing two blood pressure medications, candesartan and irbesartan, had less-than-encouraging outcomes. So researchers are interested in seemingly positive results announced yesterday at the European Society of Cardiology Congress meeting and concurrently published in The Lancet.

The study, funded Swiss drugmaker Novartis, found that taking a drug called LCZ696 for three months reduced levels of an established biomarker for heart failure, an inert molecule called N-terminal proBNP peptide (NT-proBNP), by an average of 23% among individuals with diastolic heart failure—a condition in which the heart muscle relaxes too much between beats. In contrast, the comparison group, which received valsartan, a blood pressure medication Novartis makes under the trade name Diovan, saw only a 3% average reduction. The 300-person, phase 2 trial also revealed that the group receiving LCZ696 experienced a decrease in size of the heart’s left atrium—a good thing as it indicates the organ has become more efficient at pumping out blood to the body.

“Our data make a strong argument for testing this hypothesis in a large outcomes trial to determine if it is indeed effective at reducing morbidity and mortality in this disorder with a large unmet need,” says cardiologist Scott Solomon at Brigham and Women’s Hospital in Boston, who led the Novartis-funded trial.

In heart failure, which affects an estimated 2% of the US population, heart muscle cells release a hormone called brain natriuretic peptide (BNP), a natural defense against tissue scarring and that also helps the body get rid of excess sodium, thereby preventing high blood pressure. Unfortunately, an enzyme called neprilysin degrades BNP, thus preventing it from doing its beneficial work.

LCZ696 has two molecular components, one of which that inhibits neprilysin, allowing BNP to provide a boost to the heart. The other element of the drug blocks receptors for the hormone angiotensin II, preventing it from restricting blood vessels and causing high blood pressure.

Although this study produced positive results, it is still only at the very beginning of showing any promise. “This is a good start,” says John Cleland, a cardiologist at the Castle Hill Hospital in nearby Hull, UK, who wrote the accompanying editorial in the journal.  The trouble, he explains, is that to date, no large-scale trial has established the efficacy of LCZ696 in diastolic heart failure. Novartis is already plowing ahead with an 8,000-person phase 3 trial testing LCZ696 against enalapril manufactured by Merck under the trade name Vasotec, an angiotensin-converting enzyme (ACE) inhibitor, but, importantly, that trial will  focus on patients with systolic heart failure, where the heart has trouble contracting.

A future trial on  LCZ696 for diastolic heart failure would also do well to focus on quality of life indicators in its primary study goals, explains Dalane Kitzman, cardiologist at Wake Forest Baptist Medical Center in Winston-Salem, North Carolina. He adds that while the reduction in biomarker protein levels is very encouraging, quality of life measures did not improve in the LCZ696 trial. “One of the main things patients want to know is—will this drug make me feel better?” Kitzman says, referring to quality of life.

Both cardiologists also point to the somewhat worrying trend that valsartan performed almost as well as LCZ696 at the end of the nine-month trial. This could mean that valsartan works just as well as the new drug, but more slowly. Kitzman says LCZ696 should still be tested in a large trial, and adds that researchers should bear in mind the stories of previous heart failure agents when considering study results of new potential ones. “The history of heart failure treatment is checkered with many surprising reversals and unexpected outcomes.”

Image courtesy of Creations via Shutterstock

New findings raise hopes for better blood pressure lowering drugs

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A blood pressure drug in use for more than half a century might not work entirely in the way scientists had long thought. Reporting today in Nature Medicine, researchers have found in mice that spironolactone, a diuretic known to regulate hypertension through the kidneys, exerts part of its beneficial effect through the vasculature system, too.

“The blood vessel might directly contribute to blood pressure control and might be a new target for treating high blood pressure,” says Iris Jaffe, codirector of the Molecular Cardiology Research Center at the Tufts Medical Center in Boston who led the current study.

Both the 55-year-old drug sprinolactone and the newer, more selective agent eplerenone (marketed by Pfizer under the brand name Inspra) are thought to work by blocking the mineralocorticoid receptors in the kidneys to prevent sodium retention and, thus, increase water excretion. However, a handful of recent studies have hinted that the kidney does not tell the whole story. To explore the role of the vascular system, Jaffe and her colleagues created mice specifically lacking these receptors in the smooth muscle cells that line the blood vessel walls. They found that the mice had lower blood pressure as they aged, but not because of changes in salt or water handling in the kidney. Instead, the lack of vascular mineralocorticoid receptors led to a decrease in the activity of a certain class of calcium channels of the L-type variety. The change in calcium levels in turn eased the degree of smooth muscle contraction and reduced baseline tension in the blood vessels, with blood pressure lowering consequences.

“It is a comprehensive body of work using sophisticated methodology,” says cardiologist Jane Leopold, who studies how blood vessels respond to stress at the Brigham and Women’s Hospital in Boston. Since a number of calcium channel inhibitors are known to exert antihypertensive effects, “the obvious extrapolation in terms of clinical relevance is that we should be using a combination of mineralocorticoid receptor antagonists and L-type calcium channel blockers to treat hypertension associated with aging,” says Leopold, who was not involved in the latest research.

The findings also hint at the possibility of developing new therapies that target the mineralocorticoid receptors in the blood vessels while leaving the ones in the kidneys alone. A major limitation of the currently available drugs is that they often raise levels of potassium in the blood serum, leading to a condition known as hyperkalemia that causes many people to stop taking sprinolactone and epleronone. According to Jaffe, “If we can get the vascular benefits of blocking the mineralocorticoid receptor without hitting the kidney we would avoid the hyperkalemia and that might make these drugs more generally useful in bigger patient populations.”

For an interview with Jaffe, stay tuned for the September episode of the Nature Medicine podcast. Subscribe now in iTunes and your computer will automatically download the show as soon as it becomes available.

First US stem cell trial for autistic children launches today

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Families with autistic children must navigate a condition where questions outnumber the answers, and therapies remain sparse and largely ineffective. A clinical trial being conducted by the Sutter Neuroscience Institute in Sacramento, California to address this situation began recruiting participants today for a highly experimental stem cell therapy for autism. The institute plans to find 30 autistic children between ages 2 and 7 with cord blood banked at the privately-run Cord Blood Registry, located about 100 miles west of the institute.

Already one other clinical trial, with 37 total participants between ages 3 and 12 years old, has been completed in China. The researchers affiliated with Beike Biotechnology in Shenzhen, the firm that sponsored the study, have not yet published any papers from that the trial, which used stem cells from donated cord blood. Mexican researchers are currently recruiting kids for yet another type of autism stem cell trial that will harvest cells from the participant’s fat tissue.

But for each of these officially registered trials, many more undocumented stem cell therapy treatments take place for clients who are willing to pay enough. “Our research is important because many people are going to foreign countries and spending a lot of money on therapy that may not be valid,” says Michael Chez, a pediatric neurologist and lead investigator of the study at Sutter.

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Cancer drug in the works might double as reversible male contraceptive

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Researchers show off a pup fathered by a mouse that regained its fertility.

The serendipitous finding that a potential cancer-fighting compound temporarily halts sperm production in mice has seeded new hopes for a reversible male contraceptive pill. At a time when the only non-hormonal contraceptive choices for men consist of condoms and vasectomies, the finding, published today in the journal Cell, has stirred the interest of pharmaceutical companies, although it’s quite far from entering clinical trials.

Several new contraceptives that rely on steroid hormones are in the works to reduce sperm production in men. However, most products developed to date seem to carry undesirable side effects, such as acne and perturbations of cholesterol levels. So, scientists have sought to halt sperm production with compounds that do not alter hormones, targeting everything from calcium ion channels on the tails of sperm to the production of retinoic acid, a metabolite of Vitamin A that has a role in their development. A team led by Dolores Mruk at the Population Council’s Center for Biomedical Research in New York has even reported in Nature Medicine on the discovery of a chemical compound known as Adjudin that can stop sperm-forming cells from adhering to the Sertoli cells that nurture them.

The new findings announced today also describe a non-hormonal drug for stopping sperm—but contraception was the furthest thing from the minds of James Bradner and his colleagues at the Dana-Farber Cancer Institute who initially developed the experimental compound.

As we reported last year, Bradner’s team had investigated a small molecule called JQ1 for its ability to thwart cancer by acting on a protein named BRD4. They showed success in mice with multiple myeloma, and other groups soon reported similar findings in animal models of leukemia and lymphoma. Bradner has been downright evangelical about the drug ever since, shipping it to more than 250 labs worldwide, according to a profile of Bradner published last week in Nature.

As part of their homework in understanding the specificity of JQ1, Bradner’s group found that it also targeted a similar protein, called BRDT, which comes from a completely different chromosome than BRD4. In a quick survey of the scientific literature, Bradner noticed a study that linked mutations in BRDT to fertility problems in men, so he reached out to reproductive biologist Marty Matzuk of the Baylor College of Medicine in Houston to study its contraceptive effects in mice.

“This project for us started very much as a side project,” says Bradner. “We planned together to do a critical first experiment to explore the effects of JQ1 on sperm count and motility. We went right in vivo. And we were shocked at how well the drug worked.”

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Laboratory dye repurposed against protein clumps found in Huntington’s disease

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A compound already sitting on the shelves of biomedical laboratories and emergency room supply closets seems to interrupt the formation of neurodegenerative protein clumps found in Huntington’s disease, according to a preliminary animal study published today in the Journal of Neuroscience.

This versatile agent, called methylene blue, gets a mention in medical literature as early as 1897 and was used to treat, at one time or another, ailments ranging from malaria to cyanide poisoning. The US Food and Drug Administration has never formally approved it as a therapy for any illnesses. But that fact hasn’t stopped biomedical researchers from tinkering with the agent’s apparent ability to improve cognitive function. And although the new paper out today relies on a Huntington’s disease model in flies and mice, scientists are hopeful. “Because of existing knowledge of methylene blue and the fact that it’s not harmful to humans, I would hope that progress toward clinical trials could go relatively quickly,” says Leslie Thompson, a neurobiologist at University of California–Irvine and lead author on the new study.

Huntington’s disease occurs when the C-A-G sequence of DNA base pairs repeat too often on the HTT gene, resulting in an abnormally long version of the huntingtin protein, that therefore folds incorrectly and forms clumps in the brain. The illness usually begins to affect people in their 30s and 40s, causing movement problems and early death. No drug is currently available to stop the disease from progressing.

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Antibodies found in Peruvians suggest natural resistance to rabies in local vampire bats

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While attempting to better understand the exposure of rural Latin American communities to diseases harbored by bats, epidemiologists at the US Centers for Disease Control and Prevention (CDC) have stumbled upon an intriguing finding: eight people living in two tiny Peruvian villages appear to have developed antibodies against the rabies virus found in local vampire bats without any prior vaccination or treatment for the infection. This population study, the first of its kind, may provide clues to better understand how incremental exposure to rabies could lead to better vaccines or monoclonal antibody drugs.

“We think that these people were lightly bitten during the night, but were not exposed to enough of the virus to develop a full infection,” explains co-author Sergio Recuenoco, an epidemiologist at the CDC in Atlanta who published the findings today in the American Journal of Tropical Medicine and Hygiene.

The study suggests that humans are exposed to and develop antibodies against the virus without developing disease. Whether this reflects inadequate exposure or successful immune clearance of virus remains unclear, explains Ashley Banyard, a virologist at the UK Animal Health and Veterinary Laboratories Agency in Surrey, England, adding, “Personally, I believe this paper to be of great significance to the scientific community.”

The CDC initiated its survey on human exposure to bats only four years ago, prompted by new evidence at the time that these flying mammals are reservoirs of serious pathogens such as the Ebola, Nipah and Corona viruses. But unlike those viruses, virtually every known rabies infection in humans—except for a rare handful of isolated cases—has led to death. The disease causes brain inflammation, leading to a horrible end characterized by hallucinations and convulsions. Right now the only option for people infected with rabies is an expensive and painful course of therapy that can cost up to $1,000 and require five vaccine injections and an additional shot of antibodies against the virus. The World Health Organization estimates that around 55,000 people die each year from rabies, and some evidence suggests that number may climb.

Vampire bats, which can harbor rabies, generally dine on the blood of cows and pigs. But the nocturnal creatures will bite humans if their primary food sources are unavailable. And in communities like Truenococha and Santa Marta, the two Peruvian villages in the CDC study, humans are a tasty alternative during periods when farmers have sold off their livestock.

Knowing that the Peruvians had contact with local vampire bats, CDC scientists closely examined the blood samples of the eight residents. They found a mixture of neutralizing and non-binding antibodies against rabies, leading them to deduce that the individuals had overcome exposure to the virus. As Brett Petersen, another author on the study and fellow a CDC epidemiologist, notes, better understanding these people’s immune responses could ultimately help scientists in overcoming rabies.

“A greater understanding of the process by which the people developed antibodies in this setting may help inform improved vaccine development or identify new targets for treatment,” he says.

Image courtesy of Daniel Streicker