February 2011 Archives
The WSJ Health Blog is reporting this afternoon that Lilly's head of neuroscience research, David S. Bredt, MD, PhD, is unexpectedly leaving the company after tomorrow. The doc's immediate exit, which is described as voluntary by a Lilly spokesperson, comes in the midst of Lilly's seriously troubled clinical-development program for anti-amyloid compounds to treat Alzheimer disease and the curious (at least to me) purchase of Avid Pharmaceuticals (for $800 million ultimately), which owned a PET amyloid tracer.
Up to the very present, Lilly seemed to be heavily, if not overly, invested in the idea that detecting and attacking amyloid is the major avenue toward the diagnosis and effective treatment of AD. In multiple posts, I begged to differ (see here, here, and here, for instance). Notably last year, Lilly scrapped its clinical development of the anti-amyloid compound semagacestat, because treated patients actually faired worse than placebo-treated patients. Then in January, at the JP Morgan conference, Lilly's CEO suggested that its other investigative anti-amyloid compound, the monoclonal antibody solanezumab, might also be associated with vasogenic edema (which makes sense, actually). Most recently an FDA panel conditionally endorsed the approval of the PET amyloid tracer, florbetapir; although the clinical utility of detecting amyloid in the brains of an aged population is, at the very least, debatable.
Bredt, 46, was evidently some kind of wunderkind in the neuroscience world, obtaining an MD and PhD from Johns Hopkins in the early 90s and thereafter serving on the faculty at UCSF until 2007, when he made the transition to Lilly. Seems like a sashay back to academia is possible, if not probable, after such an abrupt and unceremonious departure from the private sector.
Very delayed update: JNJ "poached" Bredt, said the WSJ Health Blog in March. So he remains in industry.
Two notable court rulings:
One by the Supremes, who ruled in a 6-2 decision* yesterday that the National Childhood Vaccine Injury Act of 1986 "preempts all design defect claims against vaccine manufacturers brought by plaintiffs who seek compensation for injury or death caused by vaccine side effects." The crux of the decision was the statutory text,
No vaccine manufacturer shall be liable in a civil action for damages arising from a vaccine-related injury or death associated with the administration of a vaccine after October 1, 1988, if the injury or death resulted from side effects that were unavoidable even though the vaccine was properly prepared and accompanied by proper directions and warnings,
with much parsing of the words "unavoidable" and "even though" by Justice Scalia, who wrote the majority opinion. Justice Sotomayor, along with Justice Ginsberg, "respectfully" dissented, concentrating on the same phrasing.
It should be noted that the case of the allegedly injured plaintiff, Hannah Bruesewitz, had been considered by a Special Master of the US Court of Federal Claims (aka the "Vaccine Court") in 1995. However, the Special Master denied the Bruesewitz's claims "on various grounds"; nevertheless, they were awarded $126,800 in attorney's fees and costs. The plaintiffs rejected this decision and sought recompense in a Pennsylvania state court—an action that was intended to be prevented by National Childhood Vaccine Injury Act. The crux of the plaintiffs' argument was that the vaccine design was defective.
The other decision is by Judge Glady Kessler of the US District Court for the District of Columbia, who has ruled that the Patient Protection and Affordable Care Act is constitutional. Kessler evidently poo-poohed the idea that a decision to not buy health insurance is inactivity—citing such an argument as "pure semantics." She wrote, "Making a choice is an affirmative action, whether one decides to do something or not do something." Her decision is in direct contradistinction to separate rulings made by a Virginia judge (Henry Hudson) and a Florida judge (Roger Vinson), who declared PPACA (or parts of it) unconstitutional. Kessler joins 2 other federal judges, 1 in Virginia and 1 in Michigan, who favor the wording of PPACA. To date, the judges' decisions are predicted by the party of the President who appointed them.
* Kagan "took no part."
As of February 2nd, the total number of PML cases associated with Tysabri (natalizumab) use equals 95 (since the relaunch of the drug in 2007). Risk data on the monoclonal antibody, which is a highly effective disease-modifying agent for relapsing-remitting MS, comes by way of comarketer Biogen Idec, which recently disclosed to news sources that 10 patients developed the life-threating brain infection last month. Four of these patients may have died, according to Reuters, bringing the total number of Tysabri-related cases of fatal PML to 20.
The overall rate of PML with Tysabri use is now calculated at 1.6 per 1000 patients. Unfortunately there is no reported information on the duration of treatment in the newly affected patients with PML. It is a vital piece of missing data, given that the risk of PML with Tysabri use increases substantially after 18 months of treatment: from 0.1 per 1000 after 12 monthly infusions to 1.64 per 1000 after 25 monthly infusions.
According to Biogen Idec's annual report for 2010, approximately 56,600 patients were receiving Tysabri worldwide as of December 31st. Last year's product revenues for Biogen Idec, which shares Tysabri income with developer Elan, were $900 million—a 16% increase over 2009 revenues.
PML = progressive multifocal leukoencephalopathy.
By drawing mostly from cited data at Dr. Zebra, a list of presidential ailments is compiled in honor of our nation's all-too-mortal Commanders-in-Chief.
1. George Washington: poor dentition, possibly due to mercury oxide treatments for various infectious diseases
2. John Adams: depression; hypochondria
3. Thomas Jefferson: recurrent, persistent headaches; chronic back pain
4. James Madison: psychogenic epilepsy; chronic biliousness
5. James Monroe: recurrent malaria; possible pulmonary tuberculosis
6. John Quincy Adams: cerebrovascular disease
7. Andrew Jackson: smallpox; malaria; heart failure
8. Martin Van Buren: alcoholism; obesity; gout
9. William Henry Harrison: generally healthy; died of pneumonia
10. John Tyler: transient, generalized paralysis—possibly Guillain Barre syndrome; cerebrovascular disease (TIAs, stroke)
11. James K. Polk: generally healthy; died of cholera
12. Zachary Taylor: yellow fever; recurrent malaria
13. Millard Fillmore: generally healthy (medical history as boring as his Presidency)
14. Franklin Pierce: chronic depression; alcoholism; tuberculosis
15. James Buchanan: blepharospasm?; alcoholism
16. Abraham Lincoln: malaria; depression; smallpox
17. Andrew Johnson: typhoid fever
18. Ulysses S. Grant: alcoholism; tobacco abuse
19. Rutherford B. Hayes: generally healthy (see Millard Fillmore)
20. James Garfield: malaria
21. Chester Arthur: alcoholism; Bright’s disease; hypertension
22. Grover Cleveland: obesity; alcoholism; tobacco abuse; cancer of the jaw
23. Benjamin Harrison: recurrent “breakdowns” or “nervous collapse”
25. William McKinley: generally healthy; possible bout of influenza (“grippe”)
26. Theodore Roosevelt: severe myopia; unilateral deafness; overweight (if not obese)
27. William H. Taft: morbid obesity; gout; sleep apnea
28. Woodrow Wilson: possible dyslexia; cerebrovascular disease
29. Warren G. Harding: recurrent mental illness; tobacco abuse; cardiovascular and cerebrovascular disease
30. Calvin Coolidge: chronic depression
31. Herbert Hoover: cholecystitis; intestinal cancer
32. Franklin D. Roosevelt: polio; hypertension; cerebral hemorrhage; possible melanoma
33. Harry S. Truman: paralytic diphtheria as child; presbyopia; cardiac failure
34. Dwight D. Eisenhower: history of tobacco abuse; Crohn disease; coronary artery disease; cerebrovascular disease
35. John F. Kennedy: chronic back pain; possible autoimmune endocrine deficiency (hypothyroidism, Addison disease)
36. Lyndon B. Johnson: coronary artery disease; cholecystitis and/or cholelithiasis
37. Richard M. Nixon: venous thromboembolism; possible blepharospasm; cerebrovascular disease
38. Gerald Ford: tobacco abuse; tongue abscess due to Actinomycetes; coronary artery disease
39. James Carter: hemorrhoids
40. Ronald Reagan: myopia; chronic prostate problems; colon cancer; Alzheimer disease
41. George H. W. Bush: history of “bleeding ulcers”; atrial fibrillation; Graves disease
42. William J. Clinton: gastroesophageal reflux disease; coronary artery disease
43. George W. Bush: hemorrhoids; alcoholism; substance abuse; syncope; colonic polyps
44. Barack Obama: tobacco abuse
On Monday, the investigative committee of the National Research Council released its review of the FBI's scientific evidence in the Amerithrax case. The conclusion: The evidence wasn't strong enough to identify flask RMR-1029 at USAMRIID in Fort Detrick, MD, as the only possible source of the Bacillus anthracis spores that were used in the attacks. The implication: That the evidence against Bruce Ivins, the USAMRIID scientist identified by the FBI as the perpetrator of the anthrax attacks, is weaker than originally proposed by the investigative agency.
But in rebuttal to the NRC report, the FBI stated Tuesday that "it was the totality of the investigative process that determined the outcome of the anthrax case." Rightly so.
It is crucial to remember that there was other compelling circumstantial evidence in the Amerithrax case, which—when taken in conjunction with the fact that flask RMR-1029 was one possible source of the anthracis spores—strongly points to Ivins. Part of that evidence is this: USAMRIID was the only relevant lab in the geographic area where the "federal eagle" envelopes that were used in the attacks were distributed and sold.
Other important evidence implicating Ivins is that 1) he worked alone in late-night shifts during September 14-16, 2001, and from September 28 to October 5, 2001, before the rounds of Post/Brokow and Leahy/Daschle letters were respectively mailed; and 2) Ivins, in highly disingenuous fashion, submitted "unusable" and false B. anthracis spores to the FBI for testing.
And, depending on how much emphasis you place on general weirdness, the guy was scarily weird. To wit, see posts "Allegation: Ivins's 1983 Letter as Former Colleague" and "Bruce Ivins as KKΓ-Obsessed "jimmyflathead."
Scanning electron micrograph of spores of Ames strain of B. anthracis from CDC/Janice Haney Carr.
A word of caution about a much-publicized study suggesting a neuroprotective benefit of eating a lot of anthocyanin-rich berries. Although the study, distributed by way of press release and scheduled to be presented at the upcoming AAN meeting, found a gee-whiz 40% reduction of Parkinson disease in men who ate a lot of berries, the absolute rates of disease had to be very small.
Among 49,281 men and 80,336 women followed up for 22 years, there were only 805 cases of PD—for an overall rate of disease at about 0.6%.* So the absolute rate reduction (which isn't given in the lay press reports) has to be tiny—probably less than 1%. For instance, if about 0.4% of men who ate a lot of berries developed PD, and 0.8% of men who didn't eat a lot of berries got PD, the relative risk reduction would equal an impressive-sounding 50%. However, the absolute risk reduction associated with berry eating would be only 0.4%.
Another head-scratching facet of this story is that the supposed neuroprotective effect of eating berries was seen only in men—a fact that suggests a statistical fluke rather than a sound finding. In fact, the only reason that this story has any credence is the speculation that anthocyanin, a flavanoid, has some neuroprotective, antioxidant effect—an effect that really shouldn't be confined to men.
All of that said, however: It probably doesn't hurt to eat a decent, weekly share of berries.
* About 500,000 people in the United States have PD, for an overall prevalence of about 0.2%.
Image of 1886 drawing of PD patient by neurologist Sir William Richard Gowers from Wikimedia Commons.
The next Javier Bardem—meaning the next Latin actor with universal appeal—is the oh-so-hot-blooded Edgar Ramirez, a multilingual Venezualan actor who lends a definite full-body swagger to his portrait of the notorious Venezualan terrorist Carlos the Jackal. The buzz-worthy Sundance mini-series, "Carlos" (2010), distills in saltatory fashion a series of outlandish terrorist acts of the 70s, most of which were spearheaded by Carlos and all of which are worth remembering for their absolute brazenness. Remember the 1975 OPEC meeting? The seemingly innumerable bombings and airline hijackings? The message: European terrorism, and all the slippery attempts to deal with it, has a sad, long history.
In November, BMS and Pfizer halted a large phase 3 study of their factor Xa inhibitor apixaban in patients with acute coronary syndrome (ACS), because of excess bleeding with the drug. It was a serious blow to the development program of a potentially viable alternative to existing, old-as-dirt anticoagulants, like heparin or warfarin. But the halted study, APPRAISE-2, was just 1 of 9 industry-sponsored trials assessing the potential benefits of apixaban in patients at risk of ischemic events. The companies were investigating the drug in other at-risk populations, like patients with a-fib or venous thromboembolism.
Now the highly favorable results of one of those studies, AVERROES, has been published in the NEJM.* In the double-blind study of 5599 patients with a-fib who were deemed unsuitable for warfarin therapy, apixaban (5 mg BID) reduced the risk of stroke by 55%, when compared with aspirin therapy (81-324 mg QD) at about 1 year (stroke rate, 1.6% vs 3.7%). There was also a statistical trend toward the reduction of death with apixaban (3.5% vs 4.4%; P = .07). Rates of major bleeding were nonsignificantly higher with the new agent (1.4% vs 1.2%). The number of intracranial bleeds were 11 with apixaban and 13 with aspirin. Apixaban may also provide some cardiovascular protection, as evidenced by the relative reduction of hospitalization for CV causes (12.6% vs 15.9%; P < .001).
The study, by design, may have been an easy score for BMS and Pfizer, because the comparator drug was aspirin in a population known to be at increased risk of stroke. But another study (ARISTOTLE) is comparing the investigational agent with standard-of-care warfarin. Study completion, according to clinicaltrials.gov, is expected in April.
ARISTOTLE = Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation; AVERROES = Apixaban Versus Acetylsalicylic Acid [ASA] to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment.
* The results were published ahead of schedule because the study was terminated early, in February of 2010, owing to the protective benefit of apixaban in patients with a-fib.
Horizontal CT image of massive, acute right hemispheric brain infarct with midline shift from Wikipedia.
Because I am a subscriber to Neurology (as an active member of the American Academy of Neurology), this e-mail popped up in my inbox yesterday.
Dear Readers of Neurology,
A story aired last night on World News Tonight with Diane Sawyer disclosing that Dr. Kenneth Shay was on the payroll of, or a consultant to, Proctor and Gamble at the time he peer-reviewed an article authored by Dr. Sharon Nations that was published in 2008 in Neurology, the medical journal of the American Academy of Neurology.
Neurology has a well-established and well-known policy at http://www.neurology.org/site/misc/info_review.xhtml that authors and reviewers must disclose conflicts of interest. Dr. Shay did not disclose any conflict of interest to the Editor-in-Chief of Neurology. Furthermore, it appears that Dr. Shay improperly shared the manuscript authored by Dr. Sharon Nations to Proctor and Gamble, in violation of the journal's confidentiality policy. The American Academy of Neurology considers any violation of these ethics policies to be egregious misconduct, and the Academy's General Counsel is reviewing its options with the editors.
Physician reviewers must disclose all conflicts of interest in order to maintain the integrity of Neurology, which is the world's most widely read and highly cited peer-reviewed neurology journal.
Regarding reports that the publication of Dr. Nations' article was delayed by two years, much of the delay was a result of the time it took the authors to resubmit a revision; the editorial office's review procedure was in line with standard time frames.
We hope you continue to enjoy reading Neurology. We welcome feedback at journal@neurology.org on this and any other issues.
Robert A. Gross, MD, PhD, FAAN
Editor-in-Chief
Neurology
The e-mail refers to this formulaic write-up (ABC News's "Cuomo on the Case"*) of a class-action personal-injury suit, in which plaintiffs are alleging that zinc in Fixodent denture cream (made by P&G) caused their neurologic damage.
The peer-reviewed article in question, published in Neurology in 2008, was featured at this blog (here), at the time of its publication. The study, a small case report, described 4 patients who developed myeloneuropathy (much like what would be expected with severe vitamin B12 deficiency) due to zinc overload (which chelates copper). The subjects, as it turns out, were massive consumers of zinc-containing denture cream (like 2 tubes per day).
Dr. Kennethy Shay, a dentist, was evidently one of the peer reviewers of the Neurology article, who (according to Dr. Gross's e-mail) failed to disclose his financial tie(s) to P&G. In the ABC News piece, the authors of the case report claim that Dr. Shay somehow delayed publication of their study; however, Dr. Gross implies in his e-mail that this was not so.
* !
Ugh. More potentially amazing medical science by way of press release, rather than peer review.
Yesterday's Guardian reported that Oxford scientists have "successfully" tested a universal influenza vaccine, which could replace (or more likely, complement) seasonal inoculations. The vaccine, unlike current formulations, is targeted against essential core proteins (namely, nuceloprotein and matrix protein 1) that are common to most influenza A virus strains, rather than the variable surface proteins (designated by the "H" and "N" in virus names). The new vaccine is also intended to produce a protective T-cell response, instead of a traditional antibody response.
The major caveat to this story (in addition to the fact that the study results have not been published in a peer-reviewed journal*) is that the Oxford team has tested the new vaccine on only 11 individuals, who were then subjected to the Wisconsin strain of the H3N2 influenza A virus. The subjects' (flu-like) symptoms—if they occurred—were compared with those of 11 unvaccinated, but virus-exposed, people.
The team reported that the new vaccine was clinically protective and boosted activated T cells; although detailed results are not provided by the newspaper. Other important take-aways from this premature story:
- The Oxford scientists are speculating about combining the new T-cell vaccine with the traditional antibody-boosting strains to promote complementary forms of immunity against influenza A.
- A T-cell response may be an important way of complementing vaccine-induced immunity in the elderly, who tend to produce less robust antibody responses to vaccines.
- A much larger trial of the new vaccine, with "several thousand" people, is anticipated.
* Although the results have reportedly been submitted to an unidentified journal.
Any country that's worth being in has an illegal-immigrant problem, and Belgium is, evidently, no exception. In Illegal (2010), director Olivier Masset-Depasse shows how a single Belarusian mom (Anne Coesens) is suddenly confined to a purgatory-like detention center in Belgium. Her protracted struggle to fight extradition is informed by her bond with her still-at-large teenage son, who can only be parented through sporadic phone calls.
Among other things (including a faultless performance by Coesens), Illegal shows that a nation's merits can be defined as much by the compassion of its citizens as by the desperation of its illegal residents.
Although
I would argue that any athlete who is suspected of sustaining a brain injury should be eliminated from further play, regardless of the outcome of any sideline assessment, a new, brief test may provide a practical way of assessing sports-related head injuries on the fly.Writing in this week's Neurology, researchers from the University of Pennsylvania and various Illinois facilities report on the utility of the 2-minute King-Devick test, which requires a brief series of rapid left-to-right number readings. In a study population of 39 boxers and other "mixed martial arts" fighters (nearly all of which were male), K-D test performance, measured in seconds, deteriorated significantly from baseline after some kind of head trauma (~11-second worsening) and even moreso after loss of consciousness (18-second worsening) during bouts. (Fighters without injury actually showed minor post-play improvement in their test scores.)
K-D tests results, importantly, also appeared to correlate well with outcomes of another validated, but more extensive, sideline test for head injury: the SAC portion of the Military Acute Concussion Evaluation (MACE).* The K-D authors report that prospective studies of athletes at the University of Pennsylvania are ongoing, to establish, among other things, norms of testing.
One ethical concern that I have with this intriguing study, however, is the use of boxers as subjects, an act that ostensibly endorses—or at least, turns a blind eye to—a sport that outrightly promotes head injury. I would've had fewer qualms about a study of a sport that doesn't intend head injury as an object of so-called play.
Another note: One of the coauthors, optometrist and entrepreneur Steve Devick, has a patent pending on the K-D test, which can be bought online in various plan packages (from "family" to "organizational") for $50-$1000. According to a 2004 profile piece in the Magazine of the University College of Optometry, Devick and Alan King invented the K-D test when they were fourth-year students at optometry school in 1976. As the story goes, they flipped a coin to determine whose surname would come first in the test's label.
The K-D test has a long history of being administered to early grade-school kids to assess rapid eye movements and their potential relationship to reading performance; however, the reliability of test results in this setting has been called into question.
SAC = Standardized Assessment of Concussion.
* My understanding is that the NFL uses the much-more complex and computerized Immediate Post-Concussion and Cognitive Testing [ImPACT] assessment off the field in its vulnerable players.
Weighing in with lightening speed in the NEJM,* legal scholar Mark Hall calls Judge Vinson's recent ruling on PPACA "far and away the most prominent decision issued to date in this ongoing litigation." The reason for the ruling's prominence, at least in part, is because the suit involved 26 plaintiff states, Hall argues. I would also propose that Vinson's ruling, despite gutting PPACA and leaving healthcare reformists at square one, is notable for its even-handedness and understandability.
Nevertheless, Hall reminds us: Florida et al vs HHS et al "is only one of about two dozen legal challenges across the country." Of the 4 suits in which federal decisions have been rendered so far,** the judgments are split: two in favor of PPACA (in Detroit and Lynchburg, VA); and two against (in Richmond, VA, by Judge Hudson, and in Pensacola, FL, by Vinson). Hall says that the judges' decisions are consistent with the party of the President who appointed them.
The unifying crux of the rulings is whether the judges buy into the notion that commercial inactivity (ie, not buying insurance) actually constitutes activity. What is being uniformly rejected, however, by the 4 judges is the government's argument that the penalty on an individual for not buying insurance is, in effect, a tax—an argument proposed by Yale law professor Jack Belkin as a slam-dunk for the constitutionality of PPACA. It appears Vinson and the other ruling judges are placing heavy weight on the PPACA wording of "penalty" (as opposed to "tax"), to Belkin's likely chagrin.
The next round of appeals in these cases, as they wend their inexorable way to the Supreme Court, will begin in the Fourth and Sixth Circuits (overseeing the Lynchburg and Detroit cases, respectively). An appeal in Florida et al v HHS et al goes to the Eleventh Circuit. Hall predicts that the Supremes won't consider one of these cases until next year, or even 2013—the year before the legislated insurance mandate is to begin. "Meanwhile," Hall writes, "the work of implementing the [PP]ACA proceeds apace.
* At least in terms of medical-publication speed.
** Hall says that, of the remaining suits, the majority have been tossed on the basis of procedural grounds, and the rest are pending.
Brrrr. It's a chilly how-do-you-do for PPACA supporters.
A federal judge said yesterday that all of the Patient Protection and Affordable Care Act should be tossed because of the insurance mandate, which he views as unconstitutional. The decision by US District Judge Roger Vinson is the culmination of a sweeping suit brought by the attorneys general from a parade of mostly red states,* Florida et al v HHS et al, which sought to knock down the Obama Administration's landmark bill.
Vinson's ruling is distinct from that of Virginia's US District Judge Henry Hudson, who ruled similarly in December that PPACA's insurance mandate is unconstitutional. Hudson, however, attempted to negate the insurance mandate while leaving the rest of PPACA intact; Vinson (probably logically) tosses all of PPACA out the window after gutting its essence, the insurance mandate. "I must conclude that the individual mandate and the remaining provisions are all inextricably bound together in purpose and must stand or fall as a single unit," he wrote. "The entire act must be declared void."
Accordingly Vinson drew on his reading of the Commerce Clause and Congress's powers to penalize (or tax?) individuals for commercial inactivity (ie, not buying health insurance). He concluded, "If Congress can penalize a passive individual for failing to engage in commerce, the enumeration of powers in the Constitution would have been in vain...and we would have a Constitution in name only [emphasis added]."
Vinson is also the guy who brought up the broccoli question ("If [the federal government] decided everybody needs to eat broccoli because broccoli makes us healthy, they could mandate that everybody has to eat broccoli each week?"), which was considered by JDs from Boston University in a year-end issue of the NEJM.
Robert Lowes, writing for Medscape, has more of the story, including speculation on when the Supreme Court might consider one of the many cases challenging PPACA.
* Listed plaintiffs are officials from Florida, South Carolina, Nebraska, Texas, Utah, Louisiana, Alabama, Michigan, Colorado, Pennsylvania, Washington, Idaho, and South Dakota.
