November 2010 Archives

If you're wondering how the Boston Biomedical Research Institute views its faculty member Dr. James Sherley, the primary plaintiff in the stem-cell case of Sherley et al v Sibelius et al, look no further than the institute's web site. Last week, the president of the trustees of BBRI wrote the executive director, Charles Emerson, informing him of the trustees' unanimous decision to file a motion with the US Court of Appeals for the DC Circuit, "seeking leave to join as amicus curaie" (or friend of the court) in support of the defendants. The defendants.

The trustees' belief:

[T]hat human embryonic stem cell research offers real promise in enhancing understanding of a wide variety of human diseases, and that it has the potential to facilitate development of new and better therapies and potential cures for some of mankind's most devastating diseases. 

The trustees asked that BBRI's scientists and staff be informed of the action.

More of the story, along with relevant history, can be found at this blog (see below) and, in more comprehensive fashion, at The Great Beyond blog.

• Briefing Timeline Set in Stem-Cell Appeal
• Stem-Cell Injunction Argued in Appellate Court: Yale Law Grads on Parade
• Senate Attempted to Alter Dickey-Wicker Amendment in 2001
• Appeals Court to Life Ban on Human Embryonic Stem-Cell Research
• DoJ to Appeal Stem-Cell Ruling

Image of undifferentiated hESCs from http://www.nih.gov/catalyst/2007/07.01.01/page1.html.

Merck Serono's not out the race to market an oral pill for multiple sclerosis in the United States. Not yet. Although it appears to be hobbling, rather than running, toward some kind of finish line.

Friday the company announced that the FDA is extending its original 6-month priority review of cladribine by another 3 months. Why the FDA needs the extra review time is unclear, but a company spokesperson told Bloomberg that the agency is not requesting additional clinical trials.

The prospect for cladribine's FDA approval remains murky, given a thumbs-down opinion from the European Medicines Agency in September. However, the drug is currently approved for the treatment of MS in Russia and Australia.

In September, the FDA approved Novartis's oral MS pill, Gilenya, with a number of safety caveats—including the institution of a REMS (Risk Evaluation and Mitigation Strategy) program and a pregnancy registry. The drug is priced at $4000 per month, wholesale, with a company-sponsored program to (slightly) ease the financial burden for patients. The web site destinationrx.com offers 30, 0.5-mg capsules for $4268.16.

At the blog/web site inThought (from Wolters Kluwer Pharma Solutions; sign-up required), the immediate uptake of Gilenya is anticipated to be tempered by neurologists' concerns about safety and cost. But the company still expects worldwide sales of $1.5 billion by 2017.

Merck Serono's hobbled racehorse, still standing.

Call Northside 777

(1948): Another hybrid of film noir and neorealism. With Jimmy Stewart as a cynical reporter (is there any other kind?) and Richard Conte (The Godfather) as a very sympathetic Polish immigrant who is convicted of murdering a Chicago cop during Prohibition. Based on the real-life conviction and exoneration of Joseph Majczek* and cleverly adapted in docudrama style for the screen, Northside 777 is a strong example of the cinematic transition toward verisimilitude—by featuring on-site filming, relatively understated acting, and (then) state-of-the-art technology.

* Read a synopsis of true events at Northwestern's Center for Wrongful Convictions.

Advanced Cell Technology, of Marlborough, Mass., announced yesterday that it received an FDA thumbs-up to begin a small clinical trial of human embryonic stem cells (hESCs) in a rare eye disorder. The trial is the second study of hESCs in humans to get a regulatory nod, making the idea of hESC therapy less and less of a sci-fi fantasy—and more and more of a threat to those who judge the potential benefit of hESC to be merely speculative.

The disorder of interest, Stargardt's macular degeneration, which affects about 30,000 Americans, is potentially a springboard for the study of hESCs in age-related macular degeneration (AMD), which affects nearly 2 million Americans. Stargardt's disease, an inherited blinding condition, affects the retinal pigment epithelium (RPE), which is also implicated in AMD.

Treating an eye disorder with hESCs (which are intended to replace the damaged RPE cells) is anticipated to be a relatively smooth investigatory ride, given 1) the accessibility of the eye (both to treatment and the assessment of treatment), and 2) the fact that the eye is immune privileged (making immunosuppressive therapy unnecessary).

"Long-term functional rescue" of RPEs, using hESC, has already been demonstrated in a rat model of retinal degeneration.

The cells sustained visual function and photoreceptor integrity in a dose-dependent fashion without teratoma formation or untoward pathological reactions. Near-normal functional measurements were recorded at >60 days survival...

Image of undifferentiated hESCs from http://www.nih.gov/catalyst/2007/07.01.01/page1.html.

Specifics are lacking, but geneticist and physician Anil Potti now takes "full responsibility for a series of anomalies in data handling, analysis and management that have come under scrutiny in the past months." Potti's mea culpa and resignation from Duke University is delivered by way of Hunt Willard, director of the university's Institute for Genome Sciences and Policy, through today's Duke Chronicle (what I remember as being a-not-so-terrible college newspaper).

In Friday's e-mail to the IGSP staff, Willard asked faculty members to "remember, especially at this time of year, all that Anil has done to positively influence the lives of many of his colleagues, trainees, friends and patients. The loss of any member of our family is difficult, and I ask you to keep that in your thoughts today." It's an overly gracious good-will sentiment generally and an insulting slap specifically to those researchers whose professional lives have been tarnished by proxy—not to mention the hopeful cancer patients who enrolled in clinical trials that were based on Potti's dubious work.

Potti had been on administrative leave from Duke since July, shortly after The Cancer Letter charged that he had seriously fudged his resume by falsely claiming to be a Rhodes scholar or "finalist." More important, Potti was facing allegations of research misconduct on the basis of a 2009 examination of his work by M. D. Anderson biostatisticians. Back-and-forth external and internal investigations ultimately led to the termination of several clinical trials, on which Potti's work was based, and the retraction of several published articles. The most recent literary casualty is a report cowritten by Potti that was published in Nature Medicine, reveals The Great Beyond Blog (presumably this article, published in 2006).

For its part in the Potti scandal, the Duke leadership (ie, President Richard Brodhead) has received sharp criticism from the blogging team (at least I think they're a team) at Duke.Fact.Checker ("Inside the Potti Mess: A Fact Checker Special Report"). The excoriation:

We do not find that Uncle Dick has taken any profile at all, that is to say exhibited any leadership. In particular, he has not expressed appropriate concern for the patients.

His only important comment came just after The Cancer Letter reported Potti's fake claim of a Rhodes Scholarship and the Rhodes Trust confirmed there was no award. With other credential issues looming at the time, Brodhead cautioned the editorial board of the [Durham] Herald-Sun not to reach rapid conclusions of truth or lie, for there could also be "intermediate explanation."

Pathetic. Dick, just pathetic. 

Photo of Anil Potti, formerly from the ISGP web site.

Deciphering the city location of Union Station (1950)—a pleasurable, but otherwise pedestrian thriller starring William Holden, Nancy Olsen, and Barry Fitzgerald—is probably more entertaining than following the kidnapping plot of a rich blind girl. The hub of action, the titular train depot, is clearly Los Angeles; but the peripheral locations—an urban stockyard, an elevated train, and the "Municipal Tunnel"—scream Chicago. It's no help that the Windy City has its own very famous Union Station (The Untouchables [1987], anyone?). The tossed-in fictional addresses (eg, 21st and Mulberry) provide no direction whatsoever.

Poster for Union Station, from Wikipedia, reproduced under fair use law.

D'oh. Color me prematurely giddy for an emerging anticoagulant market that might unseat warfarin from its dusty throne. Don't get me wrong: I'm still praising Jebus for the FDA approval of BI's Pradaxa (dabigatran)—pending some horrific and unexpected side effect that turns up in the vast postmarketing experience. And the prospects for Bayer Healthcare's Xarelto (rivaroxaban) remain excellent.

But another contender, BMS/Pfizer's apixaban just hit a big development brick wall. Excess bleeding in the APPRAISE-2 trial, a large phase 3 study of the factor Xa inhibitor (like Xarelto) in patients with acute coronary syndrome (ACS), has led to a halt of the trial, says a joint company press release. "There was clear evidence of a clinically important increase in bleeding among patients randomized to apixaban. This increase in bleeding was not offset by clinically meaningful reductions in ischemic events," wrote BMS and Pfizer.

The APPRAISE-2 trial was just 1 of 9 trials assessing the potential benefits of apixaban in patients at risk of ischemic events. Other populations in which apixaban is being investigated by the companies are a-fib patients (two phase 3 studies according to clinicaltrials.gov) and patients with venous thromboembolism (one phase 3 study per clinicaltrials.gov).

One of the phase 3 a-fib trials of apixaban (AVERROES) is in "patients who have failed or are unsuitable for vitamin K antagonist treatment" (eg, warfarin) and contains an aspirin comparator arm. The study completion date is September 2012. The other a-fib study of apixaban (ARISTOTLE), with a warfarin comparator arm, is expected to be completed in April of next year.

APPRAISE-2 = Apixaban for Prevention of Acute Ischemic Events-2.

From The Great Beyond Blog: The legitmate investigation of human embryonic stem cells (hESCs) in neurologic disease marches on. In Europe, early clinical studies of stem cells in stroke and spinal-cord injury are imminent or planned and can be added to the much-publicized, ongoing trial of stem cells for spinal injury in the United States.

Image of undifferentiated hESCs from http://www.nih.gov/catalyst/2007/07.01.01/page1.html.

For all the faults of the pharmaceutical industry (and there are many...and they are chiefly, if not solely, generated by industry marketers), it remains the site of medical innovation. In times of R&D drought, cynicism and finger wagging reign (thank you, Catherine DeAngelis, Marcia Angell, and Eric Campbell; it's been one hell of an overbearing ride). But when breakthroughs occur, life in a free-market economy gets about as sublime as it can get.

With the FDA approval of Boehringer Ingelheim's Pradaxa, patients with atrial fibrillation and their physicians now have the option to say "good riddance" to the old-as-dirt warfarin, along with its cumbersome monitoring and its pesky dose fiddling. More important, Pradaxa appears to be better at preventing stroke than warfarin in a-fib patients,* and it is not more likely to cause major bleeding, hemorrhagic stroke, or death. And Pradaxa, at its current pricing, actually appears to be cost-effective. Talk about win-win-win-win...I could go on. The only downside (at least for me) in all of this good news: BI is not a publicly traded company. This kind of innovation and company responsibility deserves investment, I say.

Forbes's Matthew Herper (The Medicine Show) may be a little less giggly in his enthusiasm, but he anticipates a Pharma resurgence with the advent of several new anticoagulants, along with Pradaxa, that will likely replace warfarin treatment. Among these is Bayer Healthcare's Xaralto (rivaroxaban), a direct factor Xa inhibitor, which may be as good as or better than warfarin for preventing stroke in a-fib patients, according to clinical data presented yesterday at the American Heart Association meeting. (Keep in mind, however, that these data have not been peer reviewed.) Other promising, warfarin-shunning candidates in development include apixiban (Pfizer/BMS), edoxaban (Daiichi Sankyo), and betrixiban (Merck).

* Although the pivotal trial, RE-LY, was powered as a noninferiority trial.

There are mixed messages from a newly published Swedish study, which examined the potential association between suicidal behavior and Accutane, but the authors correctly hedge their overall finding with some important caveats. 

The blunt-force trauma of the study is that there is a significantly increased risk of suicide attempts during the first 6 months of Accutane treatment.* According to data from Sweden's socialized-medicine database, the standardized incidence ratio** for all suicide attempts (n = 128 among 5756 treated patients) was 1.78 (95% CI: 1.04, 2.85) and that for first-time attempts was 1.93 (95% CI: 1.08, 3.18). Moreover, these incidence ratios declined after the completion of Accutane therapy (see Table). The knee-jerk conclusion: Accutane increases the risk of attempted suicide.

Time period	Incidence Ratio (95% CI)
	First Suicide Attempts	All Suicide Attempts
3 years before treatment	0.89 (0.54, 1.37)	0.99 (0.65, 1.44)
1 year before treatment	1.36 (0.65, 2.50)	1.57 (0.86, 2.63)
6 months after treatment start	1.93 (1.08, 3.18)	1.78 (1.04, 2.85)
3 years after treatment	0.97 (0.64, 1.4)	1.04 (0.74, 1.43)

However, however:

The authors stressed that the incidence ratios for attempted suicide were already increasing before Accutane therapy—for unclear reasons, but possibly as a result of despondence over progressive acne. The authors speculated,  

Considering the increasing risk of attempted suicide during the years before treatment, we cannot state whether the continued rise during and immediately after treatment was due to the natural course of severe acne or to negative effects of the treatment.

Alternative explanations for the relative increase in suicide attempts during Accutane treatment were also provided:

• Despair over a lack of acne improvement
• Despair over a lack of improvement in social life after clearing of acne

The possibility that suicidal behavior may be related to acne rather than Accutane treatment could also explain the declining ratios after the completion of therapy, when acne had cleared because of Accutane treatment. The authors concluded,

We must stress that we cannot exclude the possibility that the raised risk of suicide attempts during treatment and six months after treatment is due to the exposure to isotretinoin. However, a more probable interpretation is that the underlying severe acne may best explain the raised risk.

Supporting this conclusion is the observation that patients (n = 32) who made their first suicide attempt before treatment did not seem to have their suicidal behavior reinforced during or after Accutane treatment: Only 38% of these patients made new suicide attempts or committed suicide during follow-up. On the other hand, among the 14 patients who made a first suicide attempt during treatment or within 6 months after the end of treatment, 71% made a new attempt or committed suicide during follow-up.

* The mean length of Accutane treatment was approximately 6 months.

** The denominator was the age-, sex-, and season-adjusted background rate of suicide attempts for the population.

N.B. A previous review of the literature at this blog suggests that the risk of suicide with Accutane treatment is idiosyncratic.

Only slightly less fearsome than the Red Scare was the threat of cortisone in the 1950s. A hormonal therapy with remarkable, if mysterious, curative powers, cortisone also became known in the Eisenhower era for its troublesome mental effects. Complicating early treatment was the fact that physicians weren't quite sure how to dose the drug to supress tenacious and previously untreatable diseases.

A liberal screen adaptation of one such case study is Bigger Than Life (1956), a highly melodramatic profile of a real-life New England schoolteacher with polyarteritis nodosa. Elements of the factual account, told originally by Berton Roueché for The New Yorker in 1955, are based on the now well-known side effects of corticosteroids: grandiose mania and intense irritability. However, the screenwriters, of which there were several, crescendoed true events to biblical proportions. And star James Mason, as the patient and victim, comes close to chewing scenery—perhaps an unintended nod to the hyperphagia of treatment.

Poster image from Wikipedia and reproduced under fair use.

When using the standard cost-effectiveness threshold of $50,000 for each quality-adjusted life year (QALY) gained, Boehringer Ingelheim can justify asking up to $13.70 per day for its 150-mg dosage of dabigatran (Pradaxa). This conclusion is based on a new cost-effectiveness study, conducted by California- and Michigan-based researchers and supported by the American Heart Association and Veterans Affairs Health Services, in which the incremental benefits of preventing stroke and avoiding warfarin/protime monitoring outweighed a steep price for the new drug and the relatively elevated risks of MI.

Much of this cost-effectiveness analysis was based on data from the massive RE-LY trial and the group of at-risk enrollees with nonvalvular a-fib who were 65 years of age or older. Cost-effectiveness data were also calculated for the 110-mg dosage of dabigatran—which is not available in the United States. A lack of clinical data for the FDA-approved dosage of 75 mg bid (to be used in renally compromised patients) precludes any cost-effectiveness analysis for this regimen.

According to a November 1 press release from the company, the wholesale acquisition price for both FDA-approved doses of dabigatran will be $6.75 a day for 2 capsules (or $202.50 per month): a relative steal. Looks like retail shops can more than double their asking price and still claim a wash with the standard warfarin treatment and its attendant costs. If a post at Cafe Pharma can be believed, Walgreens is asking $169.99 for 60, 150-mg capsules; CVS, $277.99, and Walmart, $232.32.

RE-LY = Randomized Evaluation of Long-term Anticoagulant Therapy.

Eli Lilly continues to bark up the amyloid tree despite the tepid performance of anti-amyloid drugs* in Alzheimer trials. The Indiana company announced Monday that it is acquiring Avid Radiopharmaceuticals, a Philly-based molecular-imaging firm that owns florbetapir. For a total purchase price of up to $800 million, Lilly will get access to the radiolabelled (18F) tracer for PET imaging.

In recently presented (but not peer-reviewed) phase 3 results, florbetapir was shown to identify amyloid deposits in the brain and differentiate Alzheimer disease from other dementias (eg, frontotemporal dementia) in a small number of patients. According to the Indianapolis Business Journal, Lilly has been using florbetapir as a diagnostic aid in its trials of the anti-amyloid mAb solanezumab and the gamma secretase inhibitor semagacestat. (N.B. Investigation of the latter drug was abandoned by the company in August because of relatively worse cognition with the agent in late-phase AD studies. Phase 3 development of the anti-amyloid mAb solanezumab continues.)

At The Medicine Show blog, Forbes reporter Matthew Herper identifies Lilly's new acquisition as a "smart purchase." "[I]f it really is able to aide [sic] in diagnosing Alzheimer’s the market for it could be big," writes Herper. Points are also given for news that the tracer's marketing application has been submitted to the FDA.

But I'm less sanguine about the the financial outlook for florbetapir. PET imaging, amyloid tracer or no, is unlikely to be used on any kind of grand routine scale for identifying AD. Despite the fact that the condition can only be definitively diagnosed now at autopsy, recognition during life is not difficult, and AD can be clinically and radiographically differentiated from other dementia types without the use of PET imaging. Moreover, although amyloid plaques are generally more extensive in AD than in normal aging, they are not an absolute marker for the illness: At the end of the eight decade of life, up to 80% of normal-aging brains will show amyloid plaques. For the foreseeable future, I see florbetapir only as an adjunct to clinical investigation—which is just how Lilly's been using the agent.

mAb = monoclonal antibody; PET = positron emission tomography.

* Think Pfizer's and JNJ's white-knuckle development of bapineuzumab.

Photograph of atrophied brain from person with AD: National Institute on Alcohol Abuse and Alcoholism.

Today is the 115th anniversary of the first production of x-rays (thank you, Google, for the reminder) and the approximately 27th anniversary that Dr. David C.  Sabiston, Jr, pimped yours truly about their discoverer, Wilhelm Roentgen (RENT-gun). No commemoration of historic medical events seems complete without traumatic personal memories of formal education, which also include being presented on rounds with a radiograph of a buckshot shoulder (something like this, if not this) and the ever-popular ruse of showing a chest x-ray of situs inversus...backwards.

Google eases or heightens the retentive pain (depending on how jazzed you get by primary sources) by providing, in its ever-expanding Books section, access to Roentgen's original paper, "Eine neue Art von Strahlen." For those who don't read German, a translation ("On a new kind of x-rays") is provided here by the Indian Academy of Sciences.

Radiograph taken by Wilhelm Roentgen on December 22, 1895, of the hand of his wife.

At the time of its release in 1973, The Sting (hotly anticipated for its repairing of Paul Newman and Robert Redford after Butch Cassidy and the Sundance Kid [1969]) was wildly popular, and it easily grabbed the Best Picture Oscar the following year. These facts should typically preclude any justification for a remake. But there are at least 3 reasons that the story of a first-class American con should be cinematically revisited.

1. The gross miscasting of a 37-year-old Robert Redford as a "kid" apprentice grifter.
2. The anachronistic use of ragtime as the thematic background for the 1936 story.
3. The sterility of the Hollywood sets (no matter how meticulously dirtied), which are intended to substitute for a grimy Joliet, Illinois, and a big, bad Chicago.

Ooh, published just a little too late for Halloween.

Using cool, slo-mo video, German researchers showed that bats innately recognize flat surfaces, like bodies of water, through their distinctive echolocation abilities.

HT: The Great Beyond Blog.

Supplementation (or treatment, depending on your semantic viewpoint) with the omega-3 fatty acid DHA does not improve the symptoms of Alzheimer disease, according to a newly published, well-controlled study in JAMA. This latest conclusion supports results from at least 1 other similarly controlled AD study (conducted by the Karolinska Institute), which showed that DHA supplementation (along with EHA) does not improve cognition or other AD performance measures.*

In the multicenter JAMA study (conducted between November 2007 and May 2009 at 51 US sites), 402 patients with mild-moderate AD received randomly assigned DHA (2 g/d) or placebo in double-blind fashion. At 18 months of follow-up, changes in the standard measures of cognition (ADAS-cog, CDR) were not significantly different between the 2 treatment arms (in both cases with both treatments, scores increased—highlighting the importance of the placebo effect in AD). The rate of brain atrophy (via volumetric MRI in 102 subjects) was also not affected by DHA supplementation. Brain volume declined similarly with each treatment, reflecting the objective, inexorable progression of AD.

A major caveat of the study: Completion rate, 73% (295/402) was low and, according to the authors, probably related to a perceived lack of treatment efficacy.

The study, based out of Oregon Health and Science University, was supported by a grant from the National Institute on Aging and Martek Biosciences, which supplied the supplements (or treatments), the laboratory measurements (plasma and CSF measures of fatty acids), and partial funding for the MRI assessments.

ADAS-cog = Alzheimer Disease Assessment Scale , cognitive subscale; CDR = Clinical Dementia Rating; DHA = docosahexaenoic acid; EHA = eicosapentaenoic acid.

* Except in some subgroup analyses.

Image of cod liver oil capsules from Wikipedia.

It didn't receive much publicity (Times of India, anyone?), but a study demonstrating the reduction of epilepsy with statins is as intriguing as anything of late in the land of pharma. Published in last week's issue of Neurology, results of a "nested case-control study" in Canada showed that the use of statins among cardiac patients* reduced the risk of being hospitalized for epilepsy by 35% (adjusted relative risk = 0.65; 95% CI: 0.46, 0.92). Moreover the protective effect of statins appeared to be dose dependent. For every gram of atorvastatin (Lipitor) used annually, the risk of epilepsy dropped by 5%.

Nothing really new, the possibility that statins may have a neuroprotective effect—either by cerebrovascular or anti-inflammatory mechanisms—is based on some rodent studies and a spattering of studies in other patient groups (individuals with multiple sclerosis, veterans). In this study, the protective effect, whatever its mechanism, appeared to be statin specific; the reduction of hospitalization for epilepsy was not seen with nonstatin cholesterol-lowering drugs, beta blockers, or ACE inhibitors.

An accompanying editorial suggests one potentially important limitation, however, of the study: The endpoint (hospitalization for epilepsy) may have led to the overascertainment of generalized seizures and the underascertainment of partial seizures (which are more likely in the adult population). The question of whether we should prescribe statins to reduce the risk of epilepsy in persons who do not have established vascular risk factors is answered with the expected advice: Further study is needed.

N.B. Study funding was provided by the Vancouver Coastal Health Research Institute.

ACE = angiotensin-converting enzyme.

* Adults who underwent coronary revascularization procedures.

Image of Lipitor bottle from web site of Pfizer, which is currently attempting to explain an odor in some 40-mg lots of the drug.