July 2011 Archives

Far From the Madding Crowd (1967): In the mid-19th century, an earnest shepherd (Alan Bates), a reserved farmer (Peter Finch), and a dashing soldier (Terrence Stamp) vie for the love of a willful young woman (Julie Christie) along the scenic cliffs of southern England. Among any competitive male trio, it is reasonable to expect that two opponents will destroy each other (note the foreshadowing cockfight), thereby leaving the third contender to clean up. Based on the Thomas Hardy novel.

From a cinematic perspective, DP Nicholas Roeg shows a nice compositional eye for rural landscapes, while director John Schlesinger is a little too enamored with the POV shot.

Judge Royce Lamberth, the chief judge of the US District Court for DC and the guy who originally granted a preliminary injunction against stem-cell research in the case of Sherley et al v Sibelius et al (and created a lot of havoc within the NIH and among US stem-cell researchers), has now decided that it's all okay—begrudgingly. On Wednesday, Lamberth issued his ruling on a permanent injunction that makes federal funding of research with human embryonic stem cells (hESCs) legal (go here for the Nature News Blog's story).

Lamberth's decision on a permanent injunction was evidently informed by the opinions of the US Court of Appeals for the DC Circuit, which shot down Lamberth's original, preliminary injunction last April. At the heart of Lamberth's newly revised opinion is the remaining ambiguity of "research." He concludes,

...the DC Circuit has made it abundantly clear that the term is ambiguous as a matter of law. While it may be true that by following the Court of Appeals' conclusion as to the ambiguity of "research," this Court has become a grudging partner in a bout of "linguistic jujitsu," [quoting a phrase from the Appeals Court's dissenting opinion], such is life for an antepenultimate court.

And so, for the losing plaintiffs, their option is to accept Lamberth's reluctant decision or to pursue their case to the ultimate court.*

* US District Court for DC = antepenultimate court; US Court of Appeals for the DC Circuit = penultimate court; Supreme Court = ultimate court.

Forbes dishes big dirt about former CEO and micro-manager Jeff Kindler's last frazzled days at Pfizer before his abrupt ouster last December. And former HR president Mary McLeod, who used to helicopter from her home in Delaware to Pfizer HQ in Manhatten (!), comes off looking like some kind of ridiculously entitled Iago in this Shakespearean drama. Snakes, indeed. Yeesh, makes you glad to be a low-level schlemiel.*

* Excepting those huge severance packages.

A rare and poorly understood form of pediatric epilepsy, head-nodding syndrome is spreading in the new nation of South Sudan,* reports Meredith Wadman of Nature. CDC experts on site remain stumped about the cause of the apparent seizure disorder, which is associated with malnutrition, subclinical seizures, and focal brain atrophy or gliosis (aka scarring of brain tissue) in some cases. A link to endemic river blindness, or infection with Onchocerca volvulus, is tenuous, and genetic susceptibility provides only a partial explanation as to the origin of HNS.

The disease, locally called kifafa,** was first recognized in the early 1960s in Tanzania (in the East African territory of Tanganyika) by Dr. Louise Jilek-Aall (right), who founded the Mahenge Epilepsy Clinic (link to a youtube video).

For more background on HNS, click here for a 2008 article.

HT: American Academy of Neurology.

* Capital, Juba, "Jeopardy!" fans.
** Swahili for epilepsy.

Teva's launch-generic-at-risk business model is well-known. The strategy is intended to produce huge profits by making early (premature) generic drugs in the possible wake of losing, or more likely settling, patent-infringement suits. The company's most recent legal tangle on this front is with Pfizer, the paragon of big bad pharma companies, which would like to retain its patent monopoly on the blockbuster Lipitor.* Three weeks ago, Teva launched its own version of the statin in the United Kingdom, and Pfizer responded predictably (and Teva counter-responded).

But Teva also makes its own branded medicines, most notably a disease-modifying drug for multiple sclerosis, Copaxone, which provides the company with a substantial amount of revenue. According to today's WSJ, this MS drug (with a current monthly cost of more than $3500) produced $3 billion in sales last year for Teva or nearly 20% of total company's sales. And now, generic drug makers Mylan and Momenta want to produce their own versions of Copaxone, ahead of the drug's key expiration dates in 2014 and 2015. And so in response, Teva finds itself in the position of its nemesis Pfizer, by using expected legal counter-strategies to defend its still-patented cash cow.

* Which expires next year.

A new cost-effectiveness study in Neurology, the possibly legitimate methods of which elude me and an editorialist, suggests that disease-modifying drugs* (DMTs) for multiple sclerosis are not cost-effective over the long haul. This conclusion is largely informed by the very high cost of the drugs over a 10-year period, which was balanced against the benefits of the drugs for averting work loss and use of the healthcare system during the same time period. The calculated cost-effectiveness of all DMTs, expressed per the standard quality-adjusted life-year (QALY), was a staggering $800,000. For the purposes of comparison, a range of less than or within $50,000-$100,000/QALY has been generally chosen as the arbitrary benchmark for the cost-effectiveness of a medical intervention.*

While I'm not in a position to justify or criticize the methods of this study, I am able to examine the cost of DMTs in the study (Table 2) and perform simple math to conclude that the monthly price of these drugs has increased substantially—no, ridiculously—since 2008 (the year of the cited Red Book reference in the study). The following is my table comparing the average monthly costs of available DMTs for the time of the study and those supplied currently by destinationrx.com. And while jacked-up costs for these drugs over the last year are nothing new (see here, for instance), the price increases during the last 3 years are really astonishing—especially in the case of Teva's Copaxone, which has nearly doubled in price for no apparent good reason.

DMT	Average Monthly Cost 2008 Red Book	Monthly Cost July 21, 2011	Increase
Interferon beta
1b, 0.3 mg, 15 doses (Betaseron; Bayer Healthcare)	$2260.00	$3568.57	58%
1a, prefilled kit 30 μg, 4 doses (Avonex; Biogen Idec)	$2061.43	$3306.96	60%
1a, 44 μg, 6 doses (Rebif; EMD Serono/Pfizer)	$2124.27	$3048.84	44%
Glatiramer acetate, 30 prefilled syringes (Copaxone; Teva)	$1952.15	$3753.83	92%

Authors of the cost-effectiveness study wrote that reducing the cost of DMTs would have "by far the greatest impact on the cost-effectiveness of these treatments." For instance, reducing the cost of Biogen Idec's Avonex by two-thirds (to approximate the UK-based cost) would bring the cost-effectiveness value for this drug to a somewhat more rational $164,000/QALY.

* And I don't know who decided that.
** Interferons beta and glatiramer acetate (Copaxone).

Just because you can detect brain amyloid, doesn't necessarily mean that you should—at least not in clinical practice.

But that word of caution isn't stopping 3 companies from pushing forward with their late-phase development of radiolabeled* tracers for the protein—which is a pathologic signature for Alzheimer disease but is also seen, importantly, in a substantial chunk of cognitively normal elderly.

Who are we kidding? Reflection is not the bailiwick of industry.

The furthest along is Avid/Lilly's florbetapir (Amyvid), which has been the subject of many a critical post at this blog. Last word is that the company is working with the FDA to establish a reader-training program, an agency requirement for approval.

GE's flutemetamol is in phase 3 development, according to entries at clinicaltrials.gov, and the company is promoting at the current ICAD meeting 1) the tracer's comparability to the reference standard of amyloid-imaging agents, Pittsburgh compound B, and 2) the success of its own reader-training program.

Bayer's tracer, florbetaben, is just entering phase 3 study, but the compound may be the easiest to use in practice (notwithstanding the issue of knowing what to do with the results), because PET imaging may be performed up to 130 minutes after the tracer is injected.

For a recent review of the 3 amyloid-detecting compounds, see a comprehensive write-up in July's Lancet Neurology.

ICAD = International Conference on Alzheimer's Disease.

* All use 18F, which has a substantially longer half-life than the 11C-labeled Pittsburgh compound B, the reference standard for amyloid imaging. The longer, 18F-labeled amyloid tracers were developed because the short-lived Pittsburgh compound requires an on-site cyclotron. The longer-acting tracers mean that the compound can be administered and then the patient transported (if necessary) to a PET-imaging center.

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

A number of notable presentations from the ongoing International Conference on Alzheimer's Disease (ICAD) in Paris, most of it ouch-inducing for Lilly.

Dismal news about Lilly's now-defunct semagacestat: Patients with AD who took the company's experimental anti-amyloid gamma secretase inhibitor in a placebo-controlled phase 3 study remain clinically worse 7 months after stopping the drug. The take-home warning from medical pundits is that researchers should stay away from targeting gamma secretase in their zeal to clear beta amyloid, the protein that accumulates in the brains of AD patients. Lilly pulled the plug on semagacestat development in August of last year.

A protein complex, gamma secretase processes amyloid precursor protein, which produces beta amyloid. The tentative conclusion: target beta amyloid (if at all) directly. Bloomberg notes that BMS is also developing a gamma secretase inhibitor, avagacestat (BMS-708163), for the treatment of AD. The compound, in phase 2 development, may or may not be associated with a similar class-effect outcome. But...

Brain edema continues to plague clinical development of anti-amyloid compounds: Regardless of the structure or mechanism of anti-amyloid compounds, one thing appears to be consistent. They all seem to be capable of causing brain edema—probably because they all clear (or facilitate clearing of) amyloid that surrounds cerebral blood vessels. Reuters reports that 3 patients who received the experimental BMS drug developed vasogenic edema. And in January, Lilly's CEO announced that 1 patient in a solanezumab trial had developed brain edema, the adverse effect that has plagued Pfizer/JNJ's anti-amyloid mAb, bapineuzumab. Phase 3 results of Lilly's solanezumab, an anti-amyloid monoclonal antibody, are expected in the 3rd quarter of next year, but The Street isn't sanguine. Les Funtleyder, a NY-based portfolio manager and healthcare strategist, told Bloomberg that he doesn't think the drug will be approved. [A clarification to the parenthetical statement: Lilly would officially argue, if its tracer is approved to rule out amyloid-related dementia, that florbetapir is most useful for distinguishing between clinical AD that is associated with brain amyloid and non-amyloid dementias—like frontotemporal dementia. Presumably the clinical AD patients with very low levels of amyloid in this study do not have pathologically defined AD but some other kind of dementia.]

Lilly continues to put a positive spin on its neuroscience program for AD: While attempting to reassure investors that it hasn't bet everything on the idea that amyloid is the target in AD, Eric Siemers, MD, the senior medical director for the Alzheimer's Disease Team, told Bloomberg, "We haven't put all our eggs in the amyloid basket," and he talked up the company's preclinical efforts to go after tau protein, the component of AD's neurofibrillary tangles.

Nevertheless Lilly is still heavily promoting its not-yet-approved PET amyloid tracer, florbetapir (trade name, Amyvid), through the medical literature generally and the ICAD meeting specifically. The latest from ICAD is that positive scans may predict further cognitive decline in patients with mild cognitive impairment (MCI) on the basis of the existing amyloid burden in the brain. (Although, without a disease-modifying intervention, file this outcome under "What am I supposed to do with this information in practice?")

Lilly bought florbetapir, along with its manufacturer, Avid Pharmaceuticals, in November of last year for $300 million, and will fork over another $500 million if the tracer is FDA approved. In March, the agency said that it would require Lilly to establish a reader-training program to ensure the reliability of scan interpretations. The requirement was made after an FDA advisory committee recommended conditional approval of the tracer (with the indication of ruling out, not ruling in, "pathologically significant levels" of brain amyloid) in January. One month later, Lilly's neuroscience chief, David S. Brendt, MD, PhD, abruptly left the company.*

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

* Update: JNJ "poached" Bredt, said the WSJ Health Blog in March. So it appears that Bredt wasn't ousted from Lilly but was wooed by JNJ (which is developing the troubled bapineuzumab along with Pfizer).

Avid*/Lilly continues to flood the medical literature with data to ostensibly promote its PET amyloid tracer florbetapir (Amyvid). And while the company wants to give the world the impression that its tracer has diagnostic use, a repeated heaping helping of caveat emptor is appropriate.

The latest case of industry-funded promotion as peer-reviewed research: Another brain-amyloid imaging study—while showing significant differences among subjects with probable Alzheimer disease (AD), mild cognitive impairment (MCI), and other healthy controls—nevertheless also demonstrated considerable overlap in the burden of brain amyloid among these clinical subgroups. The PET data, pooled from four of the company's phase 1 or 2 clinical studies, showed that the mean value for brain amyloid (described as the cortical-to-whole-cerebellar SUVR) was significantly different among the subjects, but that also about 20% of older healthy controls demonstrate an amyloid load consistent with pathologically defined AD. And about 30% of these healthy elderly (>55 years) exhibit any level of brain amyloid, as detected with florbetapir. Conversely a substantial number of patients with clinical AD did not demonstrate pathologic levels of amyloid. (Lilly would argue that this is where its PET tracer is most useful—in ruling out AD on the basis of a low amyloid burden in suspect patients.) The amyloid burden was also significantly more likely among carriers of the APOE4 gene, for which the AD subgroup was enriched, and with each decade of life in older healthy controls.

The amyloid-overlap data are consistent with those from autopsy and other PET studies, which show, on a cumulative basis, that about 30% of cognitively normal elderly will demonstrate some level of AD-consistent brain pathology, and that many of these subjects meet the neuropathologic criteria for AD despite the absence of cognitive impairment (during life in the case of the autopsy studies).**

The $64 question for Avid/Lilly is how PET imaging for brain amyloid can be practically integrated into clinical practice, if at all. Currently the tracer appears to have its greatest use in assessing the clearing of protein in trials of investigational anti-amyloid compounds (which have their own safety problems). In the context of practice and beyond the issues of cost, PET access, and inter-reader reliability (see here, for example), the most important question is what to do when PET images demonstrate brain amyloid—given the substantial percentage of older healthy adults who demonstrate the AD-linked substance. By my read of this study, unless the florbetapir-enriched PET scan shows an amyloid burden that is undeniably above that of healthy controls or really, really low, the results are functionally useless.

* Avid is a wholly owned subsidiary of Lilly, which bought the company for $300 million and will fork over another $500 million if florbetapir ever becomes FDA approved.
** The issue of what to do with these data becomes a bit zen-like. Are these positive amyloid scans an indicator of impending AD, if the patient lives long enough? And if so, so what (especially if clinical AD is unlikely to emerge until 10 years later and/or there are no useful interventions)?
PET = positron emission tomography; SUVR = standard uptake value ratios.

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

Dark City (1950): From Hal B. Wallis, a low-budget,* but respectable, noir effort, which serves as an apparent inspiration for some of David Mamet's craftier grifter stories. A young Charlton Heston leads a small group of gambling cons (Ed Begley, Jack Webb, and Harry Morgan*) into cheating a traveling mark out of a $5000 cashier's check. Ashamed, the mark commits suicide, and the mark's unstable brother seeks murderous revenge. With Lizabeth Scott as Heston's doormat of a girlfriend and Dean Jagger (White Christmas) as a pesky police captain.

* Lots of rear projection.

** Before Webb and Morgan teamed up for "Dragnet." Working against later type, Webb pulls off contemptible snarkiness.

There are few press releases crowding my inbox that merit attention, but today's e-mail from the National Union of Healthcare Workers (NUHW), if true, is a stunner.

According to a new report from the union, the average annual combined pay and benefits* for CEOs at California's largest HMOs is $7.4 million. Million. Million.

And this obscene compensation is in the context of, as if anybody didn't already know, historic economic hardship and escalating healthcare costs. The most well-compensated execs were Wellpoint's Angela Braly ($13.1 million) and Kaiser Pemanente's George Halvorson ($7.9 million as of 2009), the CEO of the tax-exempt and ostensibly nonprofit HMO. (They earn every penny.) The president and COO of Kaiser, Bernard Tyson, according to NUHW, receives 8 separate pension and retirement plans.

Contrast these compensation packages, the NUHW says, with the average weekly income of the American worker in late 2010: $752 (or about $39,000 yearly). And after adjusting for inflation, the NUHW argues, workers are actually making less, because in part (hey, get this) a large part of inflation is due to rising healthcare costs. Before adjusting for inflation, the annual raise for the average American worker was a paltry 0.5%, says the NUHW, whereas some Kaiser execs received payment increases just last week of more than 17%.

The NUHW scolds, nay excoriates, Kaiser for "awarding its executives a king's ransom" while "raising member rates and demanding huge economic concessions from their employees who provide the health care." The apparent instigator of this executive-damning report is management's attempt to "eliminate employees' only defined-benefit pension plan."

And although the NUHW report focuses on Kaiser, the overpayment of healthcare execs isn't limited to the company (to noone's real surprise). Samuel Downing, former CEO of the Salinas Valley Memorial Healthcare District, got a cash severance of $947,594 in 2008, $3.9 million in one-time retirement payments this year, and generous ongoing payments from a regular pension plan. His base annual salary, while serving a 226-bed public hospital in Salinas, was $670,000. In an attempt to find revenue for Dowling's payout, the hospital tried to lay off 200 frontline healthcare workers, the NUHW claims. The union says that regular annual pay increases (from ~6% to ~30%) were provided to other Salinas execs between 2005 and 2010.

* Including perks like bonuses, multiple pensions, homes (homes!?), personal drivers, paid travel, access to corporate jets, and so-call gross-ups--in which execs are able to write off associated taxes on benefits.

Photo of Angela Braly from Wellpoint website.

On Friday, the CDC reported the growing resistance of Neisseria gonorrhoeae, the bacterium that causes (not surprisingly) gonorrhea, to the class of antibiotics called cephalosporins. This is concerning because, as the CDC stressed, "No other well-studied and effective antibiotic treatment options or combinations currently are available." Most recently the CDC had recommended dual antibiotic therapy for the treatment of gonorrhea in the United States, consisting of ceftriaxone (the most-effective cephalosporin for the venereal disease) and azithromycin or doxycyline. This recommendation has changed slightly on the basis of data from the CDC-sponsored Gonococcal Isolate Surveillance Project (GISP).

According to GISP, ceftriaxone-resistant N. gonorrhoeae in the United States increased threefold, from 0.1% in 2000 to 0.3% last year. And while the CDC continues to recommend ceftriaxone as part of effective therapy for gonorrhea, the agency appears to be bracing for growing antibiotic resistance—like that seen with N. gonorrhoeae and fluoroquinolones at the turn of the century. The CDC recommends that the other half of currently recommended therapy for uncomplicated gonorrhea should now consist of azithromycin (not doxycycline) because of the sensitivity/resistance patterns of the latest cephalosporin-resistant N. gonorrhoeae isolates.

The history of antibiotic-resistant N. gonorrhoeae is nearly as old as the history of antibiotics. Before the advent of antimicrobial drugs, gonorrhea was treated in a haphazard way with various concoctions, delivered either systemically or locally. One such treatment, prescribed to a victim of Elixir of Sulfanilamide, called for a mixture of zinc sulphate, lead acetate, colorless hydrastis (the herb goldenseal), and bismouth subnitrate, which was to be injected by way of a penis syringe.

Sulfanilamide was the first widely available antibiotic shown to be effective against the venereal disease (see Dees JE, Colston JAC. The use of sulfanilamide in gonococcic infections. J Am Med Assoc. 1937;108:1854-1858). But sulfonamide resistance was reported as early as the mid-1940s, and preferred therapy for gonorrhea became penicillin, until N. gonorrhoeae resistance to this mainstay emerged in the 1960s (see here, here, and here for example) and grew throughout the 1970s. Tetracycline-resistant N. gonorrhoeae emerged in the 1980s (see here for example), and fluoroquinolone-resistant bugs (eg, to ciprofloxacin, ofloxacin) showed up in Hawaii in the mid-90s.

Gram stain showing N. gonorrhoeae diplococci from the CDC/M. Rein (1978).

Vincent & Theo (1990) is a relatively mainstream effort from Robert Altman, which depicts the highly intense, symbiotic relationship between the paragon of tortured artists, Vincent Van Gogh (Tim Roth), and his younger brother, Theo (Paul Rhys), an art dealer. There are, nevertheless, recognizable elements of Altman's signature here—most notably the occasional overlapping dialog and extraneous audio. The opening of the movie, in particular, is a seamless confluence of parallel scenes from two different eras: one showing the record-setting auction of Vase with Fifteen Sunflowers at Sotheby's Christie's of London in the 1980s, and the other depicting the austere poverty and sheer lunacy of Vincent as an untrained artist, 100 years earlier. It is probably one of my favorite introductions in all of filmdom (rivaling the set-up montages of Close Encounters of the Third Kind and The Magnificent Ambersons). A brief introduction to the action at Sotheby's Christie's cuts to Vincent and Theo arguing in the artist's decrepit hovel. And while an anguished Theo maligns the meager lifestyle and preposterous, new career choice of his even more anguished brother, Altman maintains the audio of the auction's escalating bids at a low, but conspicuous, volume. With this relatively simple effect, Altman creates a kind of aural wormhole—in effect, placing the auction just outside of Van Gogh's shack.

A new meta-analysis of 14 Chantix (varencicline) trials raises safety concerns, perhaps rashly, about the short-term (≤1 year) cardiovascular risks of the drug. And while the absolute effect size with Pfizer's smoking-cessation drug, versus placebo, was tiny (1.06% - 0.82% = 0.24%), the potential cardiovascular effects of Chantix at least make more physiologic sense than some other studies proposing a short-term risk of cancer with certain antidiabetic drugs (like Actos and Avandia).

In a company press release, issued July 4th,* Pfizer said it "stands behind the benefit/risk profile of Chantix" and "expressed concerns about the reliability of the meta-analysis." Specific concerns related to the "appropriateness of the authors' measure of cardiovascular risk...which combines events that do not share a common biological cause." The probable main objection here is the inclusion of arrhythmias in the composite endpoint, which may not have anything to do with the process of vascular disease. Pfizer also stressed the small absolute difference between Chantix- and placebo-treated patients. The company reported that it plans to conduct its own meta-analysis to assess the potential cardiovascular risks of Chantix.

In June, the FDA posted a warning about the potential, albeit small, cardiovascular risks of Chantix. The warning was based on data from a 1-year, randomized, placebo-controlled trial of 700 smokers. Both the efficacy and safety results are tabulated here. Clearly Chantix improves the chances of quitting (which should lower tobacco-related cardiovascular and cancer risks—!), but short-term cardiovascular risks may also exist with use of the drug.

Outcome	Chantix (n = 350)	Placebo (n = 350)	P Value
Continuous quit rate, % (4 weeks)	47	14	<.0001
Continuous abstinence rate, % (weeks 9-52)	19	7	<.0001
Nonfatal MI, %	2.0	0.9	Not calculated
Need for coronary revascularization, %	2.3	0.9	Not calculated
Angina requiring hospitalization, %	2.3	2.3	Not calculated
New diagnosis of PVD or PVD procedure, %	1.4	0.9	Not calculated

N.B.--For the safety analysis, the n value in the Chantix arm was 353.

Notably this trial was not powered to detect statistically significant differences in the safety analysis portion of the study. The FDA affirmed that, on the basis of these data, it was "requiring the manufacturer to conduct a large, combined analysis (meta-analysis) of randomized, placebo-controlled trials" to further define the potential, short-term cardiovascular risks of Chantix.

* No holiday for public relations.

Irish actor Brendan Gleeson (In Bruges, the Harry Potter movies) has the undeniable charisma to sustain The General (1998), John Boorman's fact-inspired portrait of an affable career thief, Martin Cahill, who eventually tangles with the IRA (with predictable consequences). Jon Voight, as a Dublin police chief, takes a wise backseat to Cahill's story of brazen defiance and, occasionally, bitter desperation.