Glaxo heart drug that failed trial shows potential benefit

The GlaxoSmithKline logo is seen at the entrance of a building in Luxembourg, September 10, 2013. Picture taken September 10, 2013 REUTERS/Yves Herman

The GlaxoSmithKline logo is seen at the entrance of a building in Luxembourg, September 10, 2013. Picture taken September 10, 2013

Credit: Reuters/Yves Herman

(Reuters) – A new type of heart drug being developed by GlaxoSmithKline, which failed the main goal of a Phase III study of patients with chronic but well-treated heart disease, showed signs of potential benefit, the trial’s co-leader said.

The results presented at the American College of Cardiology scientific meeting in Washington on Sunday provided a glimmer of hope that the medicine, darapladib, may have value.

“I’m convinced there is a signal here of efficacy and the drug is safe,” said Dr. Harvey White, co-chair of the large, Glaxo-sponsored international study, who presented the findings.

The real test of darapladib is likely to come from a second, late-stage study in far less stable patients who received the medicine within 30 days of a heart attack.

A positive result in that study could put the drug back on track, after it was largely discounted by analysts and investors following the first Phase III failure.

The stakes are high for the British drugmaker as gaining full control of darapladib was one of the reasons behind its $3.6 billion acquisition of Human Genome Sciences in 2012.

Human Genome had rejected an earlier $2.6 billion offer, claiming that Glaxo was underestimating the blockbuster sales potential of darapladib.

Glaxo had previously said darapladib did no better than a placebo in decreasing the risk of a combination of cardiovascular death, heart attack and stroke in the trial called Stability.

The trial involved 15,828 patients followed for a median of 3.7 years.

For those taking the Glaxo pill, 9.7 percent had one of the major adverse events compared with 10.4 percent for the placebo, which was not a statistically significant difference.

A lack of any impact on stroke prevention appears to have contributed to the failure of the study, researchers surmised.

In addition, the effect of the Glaxo drug may have been muted by the high level of care the patients were receiving.

Almost all were taking statins and aspirin and nearly 80 percent were on blood pressure drugs – all known to decrease the risk of heart attacks, strokes and death.

“We’re setting a very high bar and we may have affected our ability to (determine) a treatment effect,” said White, director of the coronary care unit at Auckland City Hospital in New Zealand.


The drug’s impact on the secondary goals of the study was deemed “nominally significant” by researchers, meaning they saw the potential of a clinically meaningful effect despite falling short of statistical significance.

One of the secondary goals looked at the combined number of people who died from heart disease, had a heart attack, or needed urgent artery clearing procedures.

The other secondary goal studied the combined number of people who died from heart disease, had a heart attack, were hospitalized for unstable angina or required any artery clearing procedure.

“These are all things that are very important for patients,” White explained.

When isolated from the composite goals, darapladib did numerically better at delaying heart attacks.

There were 361 heart attacks in the drug group and 405 in the placebo group, although the percentage difference missed statistical significance. There were also fewer deaths among darapladib patients.

The stroke numbers by comparison were nearly identical – 154 versus 152 for placebo.

Darapladib blocks an enzyme known as Lp-PLA2, high levels of which are considered a risk factor for heart disease.

It is believed the drug changes the composition of plaque on artery walls, making it less likely to rupture and cause clogs and serious heart problems.

One sub group of darapladib patients that fared better than the overall population was smokers, who had a greater decrease in major adverse events than non-smokers.

“Previous studies showed that smokers have higher Lp-PLA2 levels, and it’s plausible that smokers may be more responsive to Lp-PLA2 inhibition,” White said.

The most common side effects with darapladib were diarrhea, and unpleasant odor in feces, urine and skin.

There was a higher rate of kidney failure reported in patients who took the Glaxo drug, but White said most researchers did not believe that was related to darapladib.

White said he was disappointed the drug failed to meet the main goal of the study, the results of which were also published in the New England Journal of Medicine.

“But there is a message here that something is going on. I wouldn’t for one moment think that there’s nothing going on here and it should be abandoned,” he said.

Glaxo, meanwhile, is pinning its hopes on the next large study in sicker patients that should have results available in two or three months.

“If in the second study you see effects on the cardiovascular end points, this is still a potentially useful drug for patients with heart disease,” Murray Stewart, Glaxo’s head of Metabolic Pathways Cardiovascular Therapy Area, said in a telephone interview.

“The main thing will be the next study.”

(Reporting by Bill Berkrot; Editing by Sophie Hares)

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Edwards heart valve system tops Medtronic version in small study

(Reuters) – The minimally invasive aortic heart valve replacement system from Edwards Lifesciences Corp performed better than a rival product sold by Medtronic Inc in the first head-to-head study of the two, according to data from a small German trial presented at a major heart meeting on Sunday.

While the results are unlikely to be seen as decisive, given the size and limited scope of the study, they could provide the Edwards sales force with a valuable marketing tool as the two companies vie for market share with their competing transcatheter aortic valve replacement (TAVR) systems.

Both systems employ a catheter to thread the new valve through an artery into place in the heart, sparing patients too frail for open heart surgery from the invasive chest cracking procedure. The Edwards Sapien XT uses a balloon to expand the compressed valve once it is in position in the diseased valve, while the Medtronic CoreValve has a special self expanding valve using an alloy that reacts to body heat to open.

In the 241-patient study conducted at five German hospitals, doctors using the Edwards balloon expandable system reported a success rate of 95.9 percent compared with a 77.5 percent success rate for those using the Medtronic alternative.

A successful procedure was defined as one in which the valve was implanted in the correct position and provided a tight enough seal to prevent blood leakage across the valve.

Patients receiving the Edwards valve also reported improvement in symptoms such as breathlessness, chest pain and dizziness 30 days after the procedure at a higher rate than those in the Medtronic group – 94.3 percent versus 86.7 percent.

“We have two main types of valves available for this procedure, and until now, there was no conclusive data about their relative effectiveness,” Dr. Mohamed Abdel-Wahab, the study’s lead investigator, said in a statement.

(Reporting by Bill Berkrot and Ransdell Pierson; Editing by Rosalind Russell)

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Nurse in court charged with murders

Victorino Chua

Victorino Chua was remanded in custody by magistrates in Manchester

A nurse has appeared in court charged with murdering three patients at Stepping Hill Hospital in Stockport in 2011.

Victorino Chua, 48, of Churchill Street, Heaton Norris, is also charged with 31 other offences including GBH and attempted poisoning.

He is accused of murdering patients Tracey Arden, 44, Arnold Lancaster, 71, and Alfred Derek Weaver, 83.

At Manchester Magistrates’ Court, he confirmed his name, age and address.

Mr Chua was remanded in custody to appear at Manchester Crown Court on Tuesday.

He faces one count of causing grievous bodily harm with intent, 22 counts of attempting to cause grievous bodily harm with intent, seven counts of attempting to administer poison and one count of causing poison to be administered with intent.

‘Public support’

Investigators have been examining the contamination of saline ampoules and bags between 1 June and 15 July 2011 at the hospital.

Mr Chua, who is originally from the Philippines, was first arrested in January 2012 and was later released on bail. He was re-arrested on Friday.

In a statement, Ann Barnes, chief executive of Stockport NHS Foundation Trust, said: “We are very much aware that at the centre of this complex and lengthy police investigation are the patients and their families affected by these events.

“Our thoughts have been with them throughout this time.

“We have always benefited from outstanding public support and confidence in our services and are pleased that this has never wavered.”

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Senegal shuts land border with Guinea to prevent Ebola spreading

(Reuters) – Senegal closed its land border with Guinea on Saturday to try to prevent the spread of the Ebola virus, which Guinean authorities say is suspected of killing 70 people in what would be the deadliest outbreak in seven years.

The discovery of 11 people suspected to have died of Ebola in Sierra Leone and Liberia in recent days has stirred concern that one of the most lethal infectious diseases known to man could spread in a poor corner of West Africa, where health systems are ill-equipped to cope.

Senegal’s Interior Ministry said it had closed the land border with Guinea in the southern region of Kolda and the southeastern region of Kedougou.

“The governors of these regions have taken all the necessary steps to implement this decision,” it said in a statement published by the official APS state news agency.

A spokesman for Guinea’s government said it had not received any official notification of Senegal’s decision. The extent of the epidemic is being exaggerated and only 19 cases of Ebola have officially been confirmed by laboratory tests, he added.

“We’ve taken strict measures to stop this epidemic and there is no reason to panic,” Damantang Albert Camara told Reuters.

Senegal announced on Friday it would introduce sanitary checks on flights between Dakar and the Guinean capital Conakry, where eight cases of Ebola have been confirmed, including one death.

West African foreign ministers said at a conference in Ivory Coast this week the Ebola outbreak posed a “threat to regional security”.

If the 70 deaths to date are all confirmed as Ebola, it would be the most deadly epidemic since 187 people died in Luebo, in Congo’s Kasai Orientale province, in 2007.


The vast majority of the cases in Guinea have been detected in the country’s remote southeast, near the border with Sierra Leone and Liberia. It took authorities nearly six weeks to identify it as Ebola, allowing the virus to spread.

The arrival of the disease this week in the capital Conakry, where hundreds of thousands of people live tightly packed in rambling shanties, marked a sharp increase in the population at risk compared with the sparsely populated villages of the forested interior.

Sakoba Keita, head of the prevention division of Guinea’s Health Ministry, said there was no cause for alarm in Conakry as the spread of Ebola could be tackled by simple sanitary steps such as regular hand washing and the quarantine of victims.

“There have been delays in applying certain measures in our health system,” Keita told a news conference, noting six medical staff were among those killed by the disease. “From today, strict hygiene measures will be observed in our hospitals.”

There is no vaccine and no known cure for Ebola, which initially induces fever, headaches, muscle pain and weakness. In its more acute phase, Ebola causes vomiting, diarrhoea and external bleeding that carry the virus outside victims’ bodies and threaten to infect anyone who touches them.

Ebola has killed more than 1,500 people since it was first recorded in 1976 in what is now Democratic Republic of Congo, but this is the first fatal outbreak in West Africa.

Guinea is deploying a mobile laboratory to the southern region of Gueckedou to speed up identification of the disease and to test samples from Sierra Leone and Liberia.

(Writing by Daniel Flynn; Editing by Gareth Jones)

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Amgen drug lowers cholesterol up to 66 percent in pivotal studies

(Reuters) – Amgen Inc’s drug from a high profile new class of experimental medicines lowered “bad” LDL cholesterol by 55 percent to 66 percent compared with a placebo in a trio of late-stage clinical trials, according to data presented on Saturday.

Amgen had previously said the drug, evolocumab, met the main goals of five late-stage trials involving some 4,000 patients by significantly outperforming placebo or another cholesterol medicine in a variety of patient populations.

Saturday’s presentation at the American College of Cardiology scientific meeting in Washington marked the first time the magnitude of LDL lowering and other details from the late stage studies were unveiled. Results of the other two Phase III studies will be presented at the meeting on Sunday.

The data also showed that two dosing regimens of the injected drug – 140 milligrams every two weeks or 420 mg once a month – were equally effective in reducing LDL levels.

“We’re seeing excellent efficacy and the safety profile appears no different than placebo, so you can’t get better than that,” Dr. Michael Koren, one of the lead investigators on two of the evolocumab studies, said in a telephone interview.

Evolocumab belongs to a highly promising class of drugs called PCSK9 inhibitors that block a protein that reduces the liver’s ability to remove LDL from the blood. They are expected to be used in patients who cannot tolerate widely used and highly effective statins, such as Pfizer Inc’s Lipitor, and in those unable to get their cholesterol levels low enough using currently available medicines.

“In terms of the LDL lowering, these drugs are as good or better than anything we have,” said Koren, who presented data from the trial called Mendel-2 at the ACC meeting.

In that 614-patient study, evolocumab reduced LDL 55-57 percent more than a placebo and up to 40 percent more than Merck & Co’s cholesterol fighter Zetia in patients not on any other cholesterol drugs.

It also helped about 70 percent of patients get their LDL down to 70 or lower, Koren said. That had been the target for high risk patients before controversial new guidelines announced last year eliminated specific target numbers.

Amgen said it will file its application seeking U.S. approval of evolocumab sometime this year. The drug is expected to compete with similar medicines also in late stages of development from Regeneron Pharmaceuticals Inc in partnership with Sanofi and from Pfizer.

Analysts have forecast eventual annual sales of $3 billion or more for each of the drugs, assuming insurers agree to pay for them. Some industry analysts expect them to cost thousands of dollars a year, far above the costs of statins.

The companies are conducting large, so-called outcomes studies to prove that the new medicines reduce heart attacks and strokes, as statins have, in addition to dramatically lowering LDL levels. The FDA has indicated that it would not necessarily wait for results from those years-long trials to approve the drugs.

Earlier this month, the FDA asked companies developing PCSK9 inhibitors to assess potential cognitive impairment side effects that have been reported with some cholesterol drugs.

“I can tell you in Medel-2 there was no (cognitive impairment) signal whatsoever,” said Koren, chief executive of the Jacksonville Center for Clinical Research in Florida.

Scott Wasserman, Amgen’s executive medical director for global development, said the same has been true of other evolocumab studies.

“We’ve looked at our data very, very carefully and are continuing to look at it very carefully in combination with the FDA. We haven’t seen any (neurocognitive) safety signals,” Wasserman said in a telephone interview.

In the study called Descartes, a 52-week trial of 901 patients already on statins or other lipid lowering medicines, evolocumab on average lowered LDL by 57 percent versus placebo.

The 329-patient, 12-week Rutherford-2 study tested the Amgen drug in subjects with familial hypercholesterolemia, a genetic condition involving extreme, dangerously high cholesterol. For those patients, who were already on statins and other lipid lowering therapies, evolocumab took down LDL levels by 59-66 percent compared with placebo.

Koren said he expects the first PCSK9 approvals to come for that patient population with additional approvals to follow for those who can’t take statins.

“It’s really the most exciting story since statins, no question, and I think that’s pretty universally held in the preventive cardiology community,” Koren said.

(Editing by David Gregorio)

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ACC: Statins Tied to Boost in Men's Sexual Function

Meeting Coverage

Published: Mar 29, 2014

WASHINGTON — Statins appeared to improved erectile function to a clinically meaningful degree, according to a meta-analysis.

Across 11 randomized trials, the average gain in subjective score on the International Inventory of Erectile Function (IIEF) was 3.4 points versus placebo or other controls (P=0.0001).

The effect “was clinically relevant,” John Kostis, MD, of Rutgers Robert Wood Johnson Medical School in New Brunswick, N.J., told reporters at a press telebriefing in advance of presentation at the American College of Cardiology (ACC) meeting here.

“It was about one-third of what to you achieve with PDE5 [phosphodiesterase] inhibitors and slightly bigger than what you see with of nonpharmacological lifestyle therapy,” he said, noting that the study was also scheduled for release online today in the Journal of Sexual Medicine.

He chalked the improved performance up to a net benefit of lipid lowering and pleiotropic effects of statins, such as endothelial function improvement, against the reduction in testosterone reported with the drugs because that hormone is made from cholesterol.

“This may effect an improvement in adherence to statin therapy,” Kostis suggested, noting that at least half of patients stopped or took much less than prescribed in prior large primary prevention studies.

But he recommended against using statins for sexual health effects in men without high cholesterol.

Rather, needing erectile dysfunction treatment may be a sign to look for cardiovascular risk factors like high cholesterol, Kostis noted.

“Over the years it’s become apparent that erectile dysfunction is an indication of decreased vascular health in men, and it’s considered by many to be a significant cardiovascular risk factor,” agreed Jeffrey Kuvin, MD, of Tufts Medical Center in Boston and vice-chair of the program committee for the ACC conference.

Kostis cautioned that the meta-analysis was small, with just 647 patients across 11 randomized trials (an average of 53 per study), and combined a variety of statins and durations of treatment (averaging 3 months).

Erectile function was the primary endpoint in all the trials, but not all had the more objective measures available for meta-analysis.

But the effect of statins remained statistically significant through sensitivity analyses for publication bias and with each study omitted sequentially.

“A big study that is well-powered, placebo-controlled, and probably factorial design to look at statins as well as PDE5 inhibitors and testosterone may clarify this question once and for all,” Kostis noted.

Kostis disclosed no relevant financial relationships with industry, though he has been an investigator on statin trials.

Primary source: American College of Cardiology
Source reference: Kostis JB, Dobrzynski JM “Effect of statins on erectile function” ACC 2014.

Crystal Phend joined MedPage Today in 2006 after roaming conference halls for publications including The Medical Post, Oncology Times, Doctor’s Guide, and the journal IDrugs. When not covering medical meetings, she writes from Silicon Valley, just south of the San Francisco fog.

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Reversing erectile dysfunction possible with lifestyle changes

Men suffering from sexual dysfunction can be successful at reversing their problem, by focusing on lifestyle factors and not just relying on medication, according to research at the University of Adelaide.

In a new paper published in the Journal of Sexual Medicine, researchers highlight the incidence of erectile dysfunction and lack of sexual desire among Australian men aged 35-80 years.

Over a five-year period, 31% of the 810 men involved in the study developed some form of erectile dysfunction.

“Sexual relations are not only an important part of people’s wellbeing. From a clinical point of view, the inability of some men to perform sexually can also be linked to a range of other health problems, many of which can be debilitating or potentially fatal,” says Professor Gary Wittert, Head of the Discipline of Medicine at the University of Adelaide and Director of the University’s Freemasons Foundation Centre for Men’s Health.

“Our study saw a large proportion of men suffering from some form of erectile dysfunction, which is a concern. The major risk factors for this are typically physical conditions rather than psychological ones, such as being overweight or obese, a higher level of alcohol intake, having sleeping difficulties or obstructive sleep apnoea, and age.

“The good news is, our study also found that a large proportion of men were naturally overcoming erectile dysfunction issues. The remission rate of those with erectile dysfunction was 29%, which is very high. This shows that many of these factors affecting men are modifiable, offering them an opportunity to do something about their condition,” Professor Wittert says.

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Eleven patients' deaths investigated

Dr Greg Furness

Interim medical director of the Northern Health Trust Dr Greg Furness said the trust is addressing the issues raised.

The deaths of five babies are among 11 under investigation at the Northern Health Trust.

The health minister told the Northern Ireland Assembly that he had been made aware of 20 cases in which the trust’s response was said to be below standard.

The patients were seen in the emergency, obstetrics, gynaecology or X ray departments.

It is not clear whether the deaths were avoidable. Edwin Poots said the trust’s response should have been better.

He said this was especially true, where cases were not identified as “serious adverse incidents”.

It is understood the babies were either born prematurely or were less than a month old.

The trust is also completing a review of about 35,000 X rays taken at the Causeway Hospital, Coleraine, County Londonderry, between 2011 and 2012.

Nine patients have been recalled. That review is now being extended across the entire health trust, involving 48,000 X rays.

Turnaround team

Antrim Area Hospital Antrim Area Hospital is one of those under the spotlight

Health Minister Edwin Poots said the cases, which date from 2008 until the present, were discovered by a “turnaround team” he had sent to the trust.

“I wasn’t happy with the Northern Trust, I wasn’t happy with the way things were being done there and that’s why I put a turnaround team in,” he said.

“We do need to offset that with the fact that the Northern Trust was dealing with tens of thousands of cases.

“The Northern Trust is in a considerably better place than when I inherited it in 2011.”

Mr Poots said Northern Ireland’s hospitals “are safe places”, but added: “Do we run perfect hospitals? We don’t.”

Maeve McLaughlin, the chair of the assembly’s health committee, said the the news of the cases was “quite alarming”.

“I think there are very serious questions [to answer],” she said.

‘Fallen short’

In a statement, the trust said it recognised that on certain occasions it had “fallen short of the standards the public should expect from us”.

“More critically, we failed to learn from these incidents. To those people affected we apologise,” the statement said.

“We have identified 20 separate incidents over a five-year period where the response by the trust was below standard. We have advised the department and welcome the minster’s statement today and his continued support.”

The statement said patients and their families had been let down.

It said it would work to try and prevent that happening in the future and was committed to “a culture of openness and transparency”.

The trust said that changing the culture was the key to turning the organisation around.

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U.S. FDA moves to offset shortage of common saline solution

(Reuters) – Moving to offset shortages of a common saline used in hospitals and dialysis centers, the U.S. Food and Drug Administration said on Friday that it will temporarily allow Fresenius Kabi USA LLC to distribute normal saline from its manufacturing facility in Norway.

The FDA said the initial shipments would help but not resolve shortages of 0.9 percent sodium chloride injection, also known as normal saline. The drug is widely used to treat patients with dehydration and other medical conditions.

The FDA said it is continuing to work with Baxter Healthcare Corp, B.Braun Medical Inc. and Hospira Inc to restore their supplies to hospitals and health clinics. The agency is also working with Fresenius Medical Care which supplies the drug to dialysis centers.

(Reporting by Toni Clarke in Washington; Editing by David Gregorio)

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