Author Archives: Elie Dolgin

Following ponatinib’s approval, leukemia drugs jockey to be first-line therapies

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Beth Galliart and her horse Austin{credit}Michelle Arani{/credit}

In June 2008, Beth Galliart was diagnosed with chronic myeloid leukemia. At the time, her doctors put her on Gleevec (imatinib), a small-molecule drug available since 2001 that is often touted as the poster child of personalized medicine. Marketed by Switzerland’s Novartis, Gleevec specifically targets the tyrosine kinase enzyme that is overactive in the white blood cells of people with leukemia. For close to nine months, the drug worked wonders for Galliart, and her blood counts returned to normal levels. But she soon started to feel tired again. A blood test confirmed that her cancer had returned.

Galliart’s doctors made a decision in March 2009 to switch her to Sprycel (dasatinib), a comparable tyrosine kinase inhibitor (TKI) from New York’s Bristol-Myers Squibb. She ended up taking that drug for only three days, though: her doctors took her off the drug when they received the results of a genetic test revealing that her cancer cells had evolved the T315I mutation in the tyrosine kinase BCR-ABL, making it impervious to all approved TKIs for the disease, including Gleevec and Sprycel. Galliart, an executive assistant at an investment firm in Silicon Valley, California, prepared herself for a risky bone marrow transplant. Her family prepared for the possibility that she might die.

Distant cousins from Kansas came to visit and say their final goodbyes. They and Galliart were picking strawberries one day in May 2009 when her phone rang. It was a clinical study coordinator from the University of California–San Francisco (UCSF) on the line. A managing partner from Galliart’s firm knew a UCSF doctor who was running a phase 1 clinical trial with an experimental agent called ponatinib. On the basis of preclinical work, this drug was thought to inhibit the mutated forms of the BCR-ABL protein that are responsible for people’s resistance to most TKIs—including the T315I mutation.

Galliart quickly enrolled in the study. A month later, she received her first dose of the drug.

Although she did suffer intense bone pain for three days after first receiving ponatinib—“It was sort of like a bomb was going off in my whole body,” recalls Galliart, 47—her cancerous blood cells have not come back since. She is now training for a half-marathon and regularly rides and jumps horses.

Fortunately, Galliart’s positive experience with ponatinib is not unique. In a phase 2 trial of 449 people with CML or the similar acute lymphoblastic leukemia (ALL) who were intolerant to other TKIs or who had a confirmed T315I mutation, around half responded favorably to the drug. The results were presented earlier this month at the American Society for Hematology meeting in Atlanta. Phase 1 trial results involving 81 participants, including Galliart, were published in late November in the New England Journal of Medicine (367, 2075–2088, 2012). Ponatinib was approved by the US Food and Drug Administration (FDA) today. It will be marketed by Ariad Pharmaceuticals of Cambridge, Massachusetts, as Iclusig.

“This drug has the potential to be a best-in-class agent that may be completely invulnerable to single-kinase-domain mutations,” says Neil Shah, the UCSF hematologist who treated Galliart. “I’m hopeful that it really will remove single-kinase-mutation–mediated resistance out of the picture.”

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Drug approval (and rejection) highlights from 2012

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Another year, another round of approvals, mixed reviews and high-profile failures. We look back on which medicines made the headlines.

GREEN LIGHT

Xeljanz (tofacitinib)

In November, the US Food and Drug Administration (FDA) approved the first oral disease-modifying drug for rheumatoid arthritis in more than a decade. Pfizer’s twice-daily pill—which works by blocking enzymes, called Janus kinases, that are involved in joint inflammation—is also being tested as a treatment for psoriasis, colitis and other diseases.

PCSK9 inhibitors

A new class of agents directed against proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of cholesterol metabolism, is moving into the last stage of clinical development. In phase 2 trials reported this year, experimental PCSK9 inhibitors from Amgen, Pfizer and Regeneron Pharmaceuticals (in partnership with Sanofi) each reduced low-density lipoprotein levels by 40–60%, on average, in various patient populations.

Kalydeco (ivacaftor)

The first drug designed to treat the underlying cause of cystic fibrosis won approval in 2012 from both European and US regulators. Although the approved therapy will only benefit those 4% of cystic fibrosis sufferers who have a specific genetic defect known as the G551D mutation, Vertex Pharmaceuticals reported interim data this year showing that the drug, marketed as Kalydeco, helped improve lung function in people with the most common mutation associated with the disease when administered in combination with an experimental agent called VX-809.

Glybera (alipogene tiparvovec)

European regulators in November approved the first gene therapy product to be used in the Western world. UniQure’s Glybera relies on an adeno-associated viral vector to deliver a functional copy of the gene that is deficient in individuals with a rare lipid-processing disease called lipoprotein lipase deficiency, which affects around one in a million people worldwide.

Aubagio (teriflunomide) and BG-12 (dimethyl fumarate)

People with multiple sclerosis now have a second oral drug option—and a third could be just around the corner. In September, the FDA approved Sanofi’s once-a-day tablet Aubagio for the treatment of relapsing forms of the disease. A week later, Biogen Idec posted positive phase 3 trial data for its own oral agent, BG-12. Both pills face competition from Novartis’s Gilenya (fingolimod), which hit the market in 2010.

T-DM1 (trastuzumab emtansine)

In November, the FDA granted priority-review designation to an antibody-drug conjugate developed in a partnership between Roche and ImmunoGen. Earlier in the year, phase 3 data showed that the therapy—a combination of the monoclonal antibody Herceptin (trastuzumab) linked to the cytotoxic agent mertansine—prolonged median survival by about six months longer than standard therapy did among women with advanced HER2-positive breast cancer.

Truvada (enofovir/emtricitabine) and Stribild

Gilead’s combination antiretroviral pill Truvada received the blessing of US authorities in July as a strategy for reducing the risk of HIV infection among adults at high risk of sexually acquired infection. A month later, Gilead scored another FDA blessing for its four-in-one drug Stribild, which packages Truvada together with two newer ingredients, elvitegravir and cobicistat, to combat the virus in HIV-positive individuals who have not received prior treatment.

Odanacatib

In July, Merck announced an early close to a 16,000-person clinical trial of odanacatib after a review of early results reportedly showed that the experimental osteoporosis drug significantly reduced the risk of bone fractures among post-menopausal women. Phase 2 data released this year similarly demonstrated that the investigational cathepsin K inhibitor increased bone mineral density by significantly more than standard therapy. Merck plans to file for regulatory approval early next year.

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Grant winner decided by ‘American Idol’-style public vote

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BOSTON — With so many topnotch research proposals seeking funding but only limited grant money to go around, deciding which among the best of the best projects to support is no easy task. What if you have a number of equally commendable applications and you don’t know how to break the tie? Usually, a panel of experts will weigh the merits of the various projects and come to some consensus behind closed doors. But in an unconventional twist, the Brigham and Women’s Hospital (BWH) has opted to let the general public act as scientific judge and jury.

After six weeks of online voting and nearly 6,500 votes cast, the decision was in. Today, the Harvard-affiliated hospital announced that a project designed to explore how best to integrate genomic sequencing into routine medical care for healthy newborns had won the inaugural BRIght Futures Prize. The project’s leader, clinical geneticist Robert Green, and his team received a $100,000 research grant from the BWH’s Biomedical Research Institute (BRI).

“I’m not sure if there’s any other example where an academic institution has allowed the public to decide to whom they’ll give some of their hard-earned, hard-raised research money,” says Jacqueline Slavik, executive director of the BRI.

“Our goal was really to engage the Brigham community at large,” adds Lesley Solomon, director of strategy and innovation at the institute. “We want the world to know about the breadth and depth of the research that goes on here.”

It may sound akin to a popularity contest, but Slavik and Solomon are quick to point out that all three finalists for the prize had gone through a rigorous, behind-the-scenes, peer-reviewed vetting process before reaching the final stage. Review committees with expertise in personalized medicine and systems immunology—the two subject areas for which the BRI solicited proposals for the prize—winnowed the list of applicants down to a series of semifinalists. Each selected applicant made an in-person pitch to the BRI’s Research Oversight Committee, which ultimately chose the three proposals that were presented to the public. The three finalists then worked together with the hospital’s public affairs team to create a series of videos and brief nontechnical descriptions about the projects that were hosted on the voting site.

“It’s a new way of trying to decide who gets the money when you have equally meritorious projects,” says Slavik. “We could flip a coin,” she quips. Instead, by engaging the public, “we achieve several goals at once,” without sacrificing scientific rigor.

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Global vaccination coverage improves, but rotavirus gap is wide

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Over the past year, Rwanda, Ghana, Malawi and Yemen have all joined the growing list of developing countries that have introduced vaccines against rotavirus as part of their standard national immunization programs. Yet the vast majority of the world’s children still remain at risk of infection by this vaccine-preventable pathogen, which can cause fatal gastrointestinal disease. And the situation isn’t much better for several respiratory diseases, either.

According to the latest global survey of routine vaccine coverage, tens of millions of children last year missed out on some or all of the basic recommended immunizations.

The rotavirus vaccine as well as the pneumococcal conjugate vaccine, which protects against Streptococcus pneumoniae, were administered to less than 15% of all kids outside the Americas and Europe, the report found. Similarly, global coverage of the Haemophilus influenzae type b vaccine, which protects against a bacterium responsible for bacteremia and pneumonia, among other diseases, was only 43% last year among youngsters, despite the shot being recommended in routine childhood vaccination schedules in more than 90% of the world’s nations.

The findings (see chart) were reported today jointly by the World Health Organization (WHO), the US Centers for Disease Control and Prevention and the United Nation’s Children Fund.

There is reason for optimism, though. More than four in five children worldwide now routinely receive the four lifesaving vaccines that the WHO began recommending in 1974. These include the diphtheria-tetanus-pertussis (DTP), bacille Calmette-Guérin, oral poliovirus and attenuated measles vaccines. By comparison, forty years ago less than 5% of all children received a full dose of the DTP vaccine, for example.

“The report offers us gold medals in some places and offers us challenges in others,” says William Schaffner, a vaccine specialist at Vanderbilt University School of Medicine in Nashville, Tennessee.

Efforts are now in place to boost all these numbers. Earlier this year, the WHO’s World Health Assembly adopted a global vaccine action plan that outlines plans to meet certain immunization target levels in every region, country and community in the world by the end of the decade.

Online trial registry proposed in Canada lacks teeth, critics say

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The Canadian government announced plans yesterday to establish a Web-based list of all clinical trials conducted in Canada. Such a nationwide registry would create a centralized source of information for patients to find studies they can join and for drugmakers to identify trial participants. However, critics charge that the initiative may do little to increase transparency and accountability in the reporting of clinical research results.

“I find it somewhat cynical that here the government is supporting a website to encourage participation in clinical trials when they allow the companies to keep that information proprietary,” says Alan Cassels, a pharmaceutical policy researcher at the University of Victoria in British Columbia. “It’s hypocritical and it’s crass.”

Currently, only trials funded by Canadian taxpayers or conducted at hospitals that receive public funds must be listed on a trial registry. (With no Canada-specific repository, such studies can be listed on any registry that is compliant with certain criteria set by the World Health Organization or the International Committee of Medical Journal Editors, including the US government’s clinicaltrials.gov, the UK-based Current Controlled Trials International Standard Randomised Controlled Trials Number Register and more than a dozen other national registries around the world.)

Drug company-sponsored trials, in contrast, carry no such mandate. South of the border, US law requires that trial investigators publically release protocols and results for all experimental drugs and devices on clinicaltrials.gov, including for privately funded trials. But in Canada, drugmakers have no obligation to publically disclose study data or register their trials—and, to many researchers’ chagrin, the announcement this week from Health Canada makes no mention of plans to change that.

Without a mandatory disclosure requirement, Kay Dickerson, director of the Center for Clinical Trials at the Johns Hopkins Bloomberg School of Public Health in Baltimore, worries that the proposed Canadian registry will do little to actually increase access to information for both patients and medical professionals. “If it’s voluntary that you register the trials it’s unlikely that you’re going to get 100% ascertainment,” she says.

Hardly registered

Matthew Herder, a health law researcher at Dalhousie University in Halifax, Nova Scotia, has been one of the most vocal advocates of a mandatory reporting requirement. In a letter sent to the Canadian Senate’s Standing Committee on Social Affairs, Science and Technology in June 2012, Herder and two colleagues argued against a “labor-intensive, time-consuming and costly” Canadian portal like the one being proposed, calling instead for Canadian trial sponsors to use a limited number of the already established websites.

“What’s needed is a stronger commitment to enforcing the requirement that people conducting clinical trials actually register in those existing registries,” Herder told Nature Medicine.

Nothing is finalized in the government’s plan. According to the press release from Health Canada, stakeholders will be able to weigh in on the proposal once it is ready, which is expected in the coming months. Still, most onlookers aren’t expecting much.

“We have a staggeringly opaque system here,” says Michael McDonald, a bioethicist at the University of British Columbia in Vancouver. “I applaud anything that brings some semblance of transparency, but I don’t just want it to be window-dressing.” He adds, “The devil is in the details.”

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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.

Drug pipeline is flush with new options for chronic constipation

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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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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.

Containment concerns persist at the proposed biosecurity lab in Kansas

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The US government continues to underestimate the potential of a dangerous pathogen escaping from a proposed BSL-4 containment biosecurity laboratory, according to an independent report published today.

A panel convened by the country’s National Research Council (NRC) concluded that an assessment completed earlier this year by the US Department of Homeland Security (DHS) overestimated the danger posed by tornadoes and earthquakes but underestimated the possibility of a disease being released by human error at the $1.14 billion National Bio- and Agro-Defense Facility (NBAF) in Manhattan, Kansas, which is slated to replace a half-century-old lab on Plum Island, New York.

“The DHS has just not established the safety of this facility,” Tom Manney, a retired Kansas State University geneticist and a member of No NBAF in Kansas, a group against the proposed facility, told Nature Medicine. “It may well be safe, but their analysis and how they’ve cherry-picked their data, and their assumptions give a very distorted and inaccurate view of it.”

Manney also thinks that Kansas politicians are selectively reading the NRC report. In a joint statement, US Senators Pat Roberts and Jerry Moran, both representing Kansas, together with the state’s governor, Sam Brownback, applauded the report’s authors for recognizing that the lab “would be a critical asset in securing the future health, wealth and security of the nation,” and they called on the DHS “to begin construction immediately.”